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WO2000063152A1 - Analogues acetyles et correspondants d'acide chicorique en tant qu'inhibiteurs de l'integrase du vih - Google Patents

Analogues acetyles et correspondants d'acide chicorique en tant qu'inhibiteurs de l'integrase du vih Download PDF

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WO2000063152A1
WO2000063152A1 PCT/US2000/004608 US0004608W WO0063152A1 WO 2000063152 A1 WO2000063152 A1 WO 2000063152A1 US 0004608 W US0004608 W US 0004608W WO 0063152 A1 WO0063152 A1 WO 0063152A1
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Prior art keywords
compound
acid
hiv
integrase
formula
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PCT/US2000/004608
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English (en)
Inventor
Terrence R. Burke
Lin Zhaiwei
He Zhao
Nouri Neamati
Yves Pommier
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The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services
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Priority to AU37054/00A priority Critical patent/AU3705400A/en
Publication of WO2000063152A1 publication Critical patent/WO2000063152A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • HIV Infection with HIV leads to the disease AIDS.
  • AIDS or Acquired Immunodeficiency Syndrome, has become one of the most feared diseases of the last quarter of the twentieth century. Typical . AIDS strikes people during their most productive years, leading to illness and death. AIDS has become a serious health problem both in the developed countries and in the developing world. Although a number of treatments for AIDS have been developed, progress has been slow for a number of reasons. One of these reasons is the tendency of HIV to develop resistance or tolerance to drug treatments.
  • Integrase is a key enzyme in the viral life cycle which is required for replication.
  • Lafemina et al. "Requirement of active human immunodeficiency virus type I integrase for productive infection of human T-lymphoid cells," J. Virol. 66, 7414-7419 (1992); Sakai et al, "Integration is essential for efficient gene expression of human immunodeficiency virus type l.” J. Virol. 7. 1 169-1174 (1993); Taddeo et al., “Integrase mutants of human immunodeficiency virus type 1 with a specific defect in integration," J. Virol. 68. 8401-8405 (1994); Engelman et al., “Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication," J. Virol. 69, 2729-2736 (1995).
  • HIV-1 integrase as a target for antiviral drugs
  • Integrase functions in a two step manner by initially removing a dinucleotide unit from the 3 '-ends of the viral DNA (termed “3 '-processing”), with the 3' -processed strands then being transferred from the cytoplasm to the nucleus where they are introduced into the host DNA (termed “strand transfer” or “integration”).
  • Radiolabeled oligonucleotide-based assays Karl et al., "The avian retroviral IN protein is both necessary and sufficient for integrative recombination in vitro," Cell, 63, 87-95 (1990); Craigie et al., "A rapid in vitro assay for HIV DNA integration," Nucleic Acid Res..
  • aryl units of these inhibitors are separated by a central linker as typified by general structure A (see below).
  • flavones flavones (Fesen et al., "Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds," Biochem. Pharm.. 48, 595-608 (1994); Kim et al., "A new flavonol glycoside gallate ester from Acer okamotoanum and its inhibitory activity against human immunodeficiency virus- 1 (HIV-1) integrase.” J. Nat. Prod..
  • CAPE-like analogues can lead to crosslinking of intracellular proteins.
  • Stanwell et al. "Cell protein cross-linking by erbstatin and related compounds," Biochem. Pharmacol.. 52, 475-480 (1996).
  • Toxicities may reflect oxidation of the catechols to reactive quinone species, accounting for the observed losses in cell viability.
  • development of integrase inhibitors either lacking the catechol moiety or modifications which overcome its toxic properties has been the focus of considerable work. Neamati et al., supra.
  • HIV-1 infected cells has been achieved by a single mutation of integrase amino acid 140, supporting previous evidence that L-chicoric acid acts by inhibiting integrase, and that it does so by interacting near the enzyme catalytic triad.
  • L-chicoric acid acts by inhibiting integrase, and that it does so by interacting near the enzyme catalytic triad.
  • King et al. "Resistance to the anti-human immunodeficiency virus type 1 compound L-chicoric acid results from a single point mutation at amino acid 140 of integrase," J. Virol.. 72, 8420-8424 (1998).
  • Another aspect of the invention is improved synthetic methods for enantiomers of chicoric acid itself, as well as its analogues and derivatives.
  • Still another aspect of the invention is the use of chicoric acid analogues and derivatives in in vivo, ex vivo, and in vitro methods for inhibiting the replication of HIV-1, either alone or together with other compounds that can inhibit the replication of HIV-1.
  • compositions comprising chicoric acid analogues and derivatives according to the invention.
  • the invention provides improved chicoric acid analogues and derivatives with activity against HIV-1 integrase.
  • the chicoric acid analogues and derivatives of the present invention block both the 3'-processing and integration reactions of HIV-1 integrase.
  • the invention also provides improved methods for synthesizing both enantiomers of chicoric acid as well as chicoric acid analogues and derivatives.
  • Figure 1 is a diagram depicting a pharmacophore, identified as
  • FIG. 1 is a diagram depicting a scheme of solid-phase synthesis for a chicoric acid analogue
  • Figure 3 shows a number of chicoric acid derivatives and analogues, their activity against integrase, their activity in the cytoprotection assay, and their cytotoxicity
  • Figure 4 shows a number of additional chicoric acid analogues with a monocarboxylic structure, their activity against integrase, their activity in the cytoprotection assay, and their cytotoxicity;
  • Figure 5 A is an autoradiograph of a denaturing 20% polyacrylamide gel showing the activity of various chicoric acid derivatives and analogues at a range of concentrations with the reactions run in Mn +2 ; inhibitor concentrations in ⁇ M are indicated above each lane; electrophoresis is in a 20% denaturing acrylamide gel showing 19-mer 3 '-processing products, the substrate 21-mer oligonucleotide, and higher molecular weight strand transfer (integration) products;
  • Figure 5B is an autoradiograph of a denaturing 20% polyacrylamide gel as in Figure 5 A with the reactions run in Mg +2 ;
  • Figure 5C is a graph showing the quantification of the results of
  • Figure 5D is a graph showing the quantification of the results of
  • chicoric acid derivatives and analogues are characterized by the following properties: (1) inhibitory activity against HIV-1 integrase; (2) antiviral activity against HIV-1 as measured in an assay that measures the effect of a compound in protecting a cell susceptible to HIV-1 infection from the cytopathic effect of HIV-1; and (3) minimal cellular toxicity.
  • Example 1 The synthesis of these analogues and derivatives of chicoric acid is described below in Example 1; the testing of these analogues and derivatives is described below in Example 2.
  • Removing one carboxyl function in the central linker preserves activity against HIV-1 integrase. Removing one carboxyl function in the central linker, leaving one carboxyl function remaining, still preserves activity even when one of the ester linkages between the central linker and the catechol moieties is replaced with an amide linkage. Similarly, removing one carboxyl function in the central linker and replacing both ester linkages between the central linker and the catechol moieties with amide linkages preserves the activity against the HIV-1 integrase.
  • the activity of the molecule against HIV-1 integrase is substantially preserved even though the hydroxyls of the catechol moieties are acetylated, although substitution of these hydroxyl moieties with methyl to produce tetramethyl ethers substantially abolishes activity. Moreover, the activity of the molecule against HIV-1 integrase is substantially preserved even though the hydroxyls of the catechol moieties are acetylated, although substitution of these hydroxyl moieties with methyl to produce tetramethyl ethers substantially abolishes activity. Moreover, the activity of the molecule against HIV-1 integrase is substantially preserved even though the hydroxyls of the catechol moieties are acetylated, although substitution of these hydroxyl moieties with methyl to produce tetramethyl ethers substantially abolishes activity. Moreover, the activity of the molecule against HIV-1 integrase is substantially preserved even though the hydroxyls of the catechol moieties are acetylated, although substitution
  • HIV-1 integrase is substantially preserved even though the carboxyl of the central linker is esterified with a methyl group. Thus, the charge of the carboxyl group is not required for activity.
  • lower alkyl is defined to mean a branched or unbranched alkyl group of 1-6 carbons.
  • the lower alkyl group is from 1-3 carbons.
  • Q is a valence bond or CH ;
  • X ⁇ is O, NH, or CH 2 ;
  • X 2 is O, NH, or CH 2 ;
  • Yi, Y 2 , Y 3 , and Y 4 are each a valence bond, O, or NH; where Yi, Y , Y 3 , or Y 4 is a valence bond, the element R l s R 2 , R 3 , or R 4 bonded to Yi, Y 2 , Y 3 , or Y 4 is a carboxy-containing moiety selected from the group consisting of carboxymethyl, carboxyethyl, carboxypropyl, carboxy small alkyl and carboxy aryl; where Yi, Y 2 . Y 3 , or Y 4 is O. the element Ri, R 2 , R 3 , or R- 4 bonded to Yi, Y 2 , Y 3 , or
  • Y 4 is each H, acetyl, propionyl, butyryl. isobutyryl, or is a moiety forming a lower alkyl carbamate or an aryl carbamate; where Yi, Y 2 , Y 3 , or Y 4 is NH, the element R R 2 , R 3 , or R- 4 bonded to Y l 5 Y 2 , Y 3 , or Y 4 is each acetyl, propionyl, butyryl, isobutyryl. small alkyl or aryl;
  • Zi and Z 2 are each H, lower alkyl, -CHO. -CO 2 H. or -CO W, where W is lower alkyl or aryl, or, alternatively, where Q is a valence bond, Zi and Z , together with the adjacent carbon atoms and Q, form a ring structure, the carbon skeleton of the ring structure being selected from the group consisting of cyclohexane, cyclohexene, cyclopentane, cycloheptane, cycloheptene, and benzene; with the proviso that where each of Yi, Y 2 . Y 3 , or Y 4 is O and all of R ⁇ , R 2 , R 3 , and RA are other than H, at least one of Zj or Z is -CO 2 H or -CO 2 W.
  • This formula includes both enantiomers where they exist.
  • each of Rj, R 2 , R 3 , and R-- ⁇ is H
  • each of Yi, Y 2 , Y 3 , and Y 4 is O
  • Xi and X are both O
  • Q is a valence bond
  • Zj and Z are both -CO H. Therefore, novel compounds according to the invention include compounds of formula (I) where:
  • Q is a valence bond or CH 2 ;
  • X] is O, NH, or CH 2 ;
  • X 2 is O, NH, or CH 2 ;
  • Y l5 Y 2 , Y 3 , and Y 4 are each a valence bond, O, or NH; where Yi, Y 2 , Y 3 , or Y 4 is a valence bond, the element Ri, R 2 , R 3 , or R 4 bonded to
  • Yi, Y 2 , Y 3 , or Y 4 is a carboxy-containing moiety selected from the group consisting of carboxymethyl, carboxyethyl, carboxypropyl, carboxy small alkyl and carboxy aryl; where Y h Y 2 , Y 3 , or Y 4 is O, the element R 1; R 2 , R 3 , or R 4 bonded to Y l5 Y 2 , Y 3 , or
  • Y 4 is each H, acetyl, propionyl, butyryl, or isobutyryl, or is a moiety forming a lower alkyl carbamate or an aryl carbamate; where Y u Y 2 , Y 3 , or Y 4 is NH, the element R R 2 , R 3 , or I ⁇ bonded to Y 1? Y , Y 3 , or Y 4 is each acetyl, propionyl, butyryl, isobutyryl, small alkyl or aryl;
  • Zi and Z 2 are each H, lower alkyl, -CHO, -CO 2 H, or -CO W, where W is lower alkyl or aryl, or, alternatively, where Q is a valence bond, Zj and Z , together with the adjacent carbon atoms and Q, form a ring structure, the carbon skeleton of the ring structure being selected from the group consisting of cyclohexane, cyclohexene, cyclopentane, cycloheptane, cycloheptene. and benzene; with the proviso that where each of Y ⁇ , Y 2 . Y .
  • Y 4 is O and all of Ri, R 2 , R 3 , and -R-4 are other than H, at least one of Zj or Z 2 is -CO 2 H or -CO 2 W; and with the proviso that where Xi and X 2 are both O, Q is a valence bond, and Z ⁇ and
  • Z 2 are both -CO 2 H, either at least one of R ⁇ . R?, R 3 , and is other than H or at least one of Yi, Y 2 , Y 3 , and Y 4 is other than O.
  • novel chicoric acid analogues and derivatives include the following:
  • Another aspect of the present invention is methods of synthesis of chicoric acid derivatives and analogues. These methods include both conventional synthetic methods and solid phase synthesis.
  • One method of synthesis of chicoric acid analogues and derivatives having two carboxyl groups in their central linkers comprises:
  • a method of synthesis of both enantiomers of chicoric acid involves reaction of the enantiomers of di-t-butyl tartrate, (+)-di-t-butyl L-tartrate or (-)-di-t-butyl D-tartrate, with 3,4-caffeoyl acid chloride.
  • Other hydrolysis methods can be used to convert the esters to the chicoric acids.
  • (+)-di-t-butyl L-tartrate can be dissolved in 3 ml of anhydrous pyridine and treated with 2 equivalents of a solution of 3,4-caffeoyl acid chloride in toluene (5 ml to 1 mmol of the tartrate) at room temperature overnight. After removal of pyridine, the residue is dissolved in toluene and evaporated under reduced pressure. Two subsequent additions and evaporations of toluene eliminate residual pyridine. The resulting material is passed through silica gel (ethyl acetate :hexane, 1 :1).
  • the method can be further generalized as shown in Example 1 , below, and in Schemes 1 and 2.
  • the acid chloride of a protected derivative of dihydroxycinnamic acid having its phenolic hydroxyl groups acylated is reacted with a diol or ethanolamine.
  • This alternative forms the desired product directly.
  • This alternative is shown in Scheme 1.
  • the desired product has no carboxyl groups, and producing the desired product requires only removing the acyl groups protecting the phenolic hydroxyls to produce the chicoric acid analogue or derivative.
  • the chicoric acid analogue or derivative thus produced has no carboxyl groups in its central linker.
  • the chicoric acid analogues and derivatives of the present invention are examples of compounds that have the generalized structure of "Pharmacophore A" ( Figure 1). In this model, these compounds are composed of three components, consisting of two aryl units and a central linker. Suitable solid-phase supports are well known in the art J.S. Eisenel & G. Jung. 'Organic Chemistry on Solid Supports," Angew. Chem. Int. Ed. Engl. 35: 17-42 (1996). Other solid-phase combinatorial methods are known in the art and are described, for example, in I. Sucholeiki, “Solid- Phase Methods in Combinatorial Chemistry," in Combinatorial Chemistry: Svnthesis and Application (S.R. Wilson & A.W. Czarnyk, eds., John Wiley & Sons, Inc., New York, 1997), pp. 119-133.
  • DCM dichloromethane.
  • NMP N-methylpyrrolidinone.
  • NMM N-methylmorpholine.
  • Et 3 P is triethyl phosphine.
  • TES tetraethylsilane.
  • Fmoc 9- fluorenylmethyloxycarbonyl.
  • R-C 2 H 5 A method of synthesis of an example of the generic compound described above as Formula (I), where Xj and X are both NH, Zi is H, Z 2 is CO H, and each of Yi, Y 2 , Y 3 , and Y is O, and each of R], R , R 3 , and -Rj is a moiety forming an ethylcarbamate, is shown in Scheme 3.
  • Chicoric acid analogues and derivatives according to the present invention can be used in in vivo methods for inhibiting the replication of HIV-1.
  • They can also be used in ex vivo and in vitro methods for inhibiting the replication of HIV-1, such as in screening methods to determine the relative susceptibility of strains of HIV-1 to integrase inhibitors and to identify resistant or possibly resistant strains to determine the appropriate course of therapy. This is discussed below.
  • Chicoric acid analogues and derivatives according to the present invention can be used in in vivo methods for inhibiting the replication of HIV-1, either alone or in combination with other drugs such as reverse transcriptase inhibitors or protease inhibitors.
  • Chicoric acid analogues and derivatives suitable for in vivo use have the following properties: (1) efficient in vitro inhibition of the integrase, as measured by the 3 '-processing and strand transfer reactions carried out by- the integrase; (2) ability to prevent replication of the HIV-1 virus in a cytoprotection assay to measure the ability of compounds to protect host cells from HIV-1 from the cytopathic effects of a virus strain; and (3) relatively low cytotoxicity on uninfected cells. Methods for assessing these properties are set forth in the Examples, namely in Example 2.
  • these methods comprise administering to a patient infected with HIV-1 a compound in a quantity sufficient to inhibit the replication of HIV-1 by detectably inhibiting the activity of HIV-1 integrase in the patient.
  • the compounds suitable for such in vivo methods include the novel compounds described above, with the addition of D-(+)-chicoric acid. Therefore, these compounds are described by formula (I), above, where:
  • Q is a valence bond or CH 2 ;
  • X 2 is O, NH, or CH 2 ;
  • Yi, Y , Y 3 , and Y 4 are each a valence bond, O, or NH; where Y ⁇ , Y , Y 3 , or Y 4 is a valence bond, the element Ri, R 2 , R , or R4 bonded to
  • Yi, Y 2 , Y 3 , or Y 4 is a carboxy-containing moiety selected from the group consisting of carboxymethyl, carboxyethyl, carboxypropyl, carboxy small alkyl and carboxy aryl; where Yj, Y , Y 3 , or Y 4 is O, the element Ri, R , R 3 , or -R t bonded to Yi, Y 2 , Y 3 , or
  • Y is each H, acetyl, propionyl, butyryl, or isobutyryl, or is a moiety forming a lower alkyl carbamate or an aryl carbamate;
  • Yi, Y 2 , Y 3 , or Y 4 is NH, the element Ri, R 2 , R 3 , or R 4 bonded to Y Y 2 , Y 3 , or Y 4 is each acetyl, propionyl, butyryl, isobutyryl, small alkyl or aryl;
  • Zi and Z are each H, lower alkyl, -CHO, -CO 2 H, or -CO W, where W is lower alkyl or aryl, or, alternatively, where Q is a valence bond, Zi and Z 2 , together with the adjacent carbon atoms and Q, form a ring structure, the carbon skeleton of the ring structure being selected from the group consisting of cyclohexane, cyclohexene, cyclopentane, cycloheptane, cycloheptene.
  • chicoric acid analogues and derivatives according to the present invention can be used alone for in vivo treatment, it is generally preferred to administer them along with other agents capable of in vivo inhibition or blockage of replication of HIV-1.
  • agents include protease inhibitors and reverse transcriptase inhibitors. The use of these agents is well known in the art and need not be described further herein.
  • Reverse transcriptase inhibitors include zidovudine (3 '-azido-3 '-deoxythymidine), didanosine (2',3'-dideoxyinosine), stavudine
  • 5-fluoro-3 '-thiacytidine 5-fluoro-3 '-thiacytidine
  • adefovir nevirapine
  • delaviridine delaviridine
  • loviride and other agents.
  • Protease inhibitors include saquinavir, indinavir, and other agents.
  • the appropriate dosages and routes of administration of these agents can be determined by the treating physician based upon such consideration as the clinical status of the patient, the weight, size, and age of the patient, the T-cell count of the patient, the particular strain of HIV-1 infecting the patient, the presence or absence of opportunistic infections, the use of other therapies, the response of the patient to the therapies, and pharmacokinetic considerations such as kidney and liver function, which can affect the metabolism and excretion of the agents being administered.
  • the chicoric acid analogues and derivatives, together with other antiviral agents if used, are administered in a conventional pharmaceutically acceptable formulations, preferably including a carrier.
  • Conventional pharmaceutically acceptable carriers known in the art can include alcohols, e.g., ethyl alcohol, serum proteins, human serum albumin, liposomes, buffers such as phosphates, water, sterile saline or other salts, electrolytes, glycerol, hydroxymethylcellulose, propylene glycol, polyethylene glycol, polyoxyethylenesorbitan, other surface active agents, vegetable oils, and conventional anti-bacterial or anti-fungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • a pharmaceutically-acceptable carrier within the scope of the present invention meets industry standards for sterility, isotonicity, stability, and non-pyrogenicity.
  • the particular carrier used depends on the concentration of the agent capable of blocking the immune defense suppressive effect and the intended route of administration.
  • a pharmaceutical composition according to the present invention is injected by one of a number of conventional routes, such as intravenous, intradermal, intraperitoneal, or intramuscular, or is administered parenterally.
  • Another aspect of the present invention is ex vivo and in vitro methods for inhibiting HIV-1 integrase or protecting susceptible target cells from HIV-1 infection. These methods are based on the assays described in the Examples for inhibition of the 3 '-processing and strand transfer reactions of the integrase, and for cytoprotection to determine the ability of these compounds to inhibit the replication of HIV-1 in susceptible target cells and thus to protect these cells.
  • such methods comprise contacting HIV-1 integrase with a quantity of a compound sufficient to produce a detectable inhibition of HIV-1 integrase.
  • the compounds are the novel compounds described above, with the addition of D-(+)-chicoric acid. Therefore, these compounds are described by formula (I), above, where: Q is a valence bond or CH ;
  • Xi is O, NH, or CH 2 ;
  • X 2 is O, NH, or CH 2 ;
  • Yi, Y 2 , Y 3 , and Y are each a valence bond, O, or NH; where Yi, Y 2 , Y 3 , or Y 4 is a valence bond, the element R 1; R 2 , R 3 , or R 4 bonded to Yi, Y , Y 3 , or Y 4 is a carboxy-containing moiety selected from the group consisting of carboxymethyl, carboxyethyl, carboxypropyl, carboxy small alkyl and carboxy aryl; where Yi, Y 2 , Y 3 , or Y 4 is O, the element R ⁇ , R 2 , R , or R-j bonded to Yi, Y , Y 3 , or
  • Y 4 is each H, acetyl, propionyl, butyryl, or isobutyryl, or is a moiety forming a lower alkyl carbamate or an aryl carbamate; where Yi, Y 2 , Y 3 , or Y is NH, the element Ri, R 2 , R 3 , or R 4 bonded to Y l5 Y 2 , Y 3 , or Y 4 is each acetyl, propionyl, butyryl, isobutyryl, small alkyl or aryl;
  • Zj and Z 2 are each H, lower alkyl, -CHO, -CO 2 H, or -CO 2 W, where W is lower alkyl or aryl, or, alternatively, where Q is a valence bond, Zi and Z 2 , together with the adjacent carbon atoms and Q, form a ring structure, the carbon skeleton of the ring structure being selected from the group consisting of cyclohexane, cyclohexene, cyclopentane, cycloheptane, cycloheptene, and benzene; with the proviso that where each of Yi, Y 2 , Y 3 , or Y is O and all of R 1?
  • R 2 , R 3 , and R-4 are other than H, at least one of Zi or Z is -CO 2 H or -CO 2 W; and with the proviso that either: (1) where Xi and X are both O, Q is a valence bond, and Zi and Z 2 are both -CO 2 H, either at least one of R R 2 , R 3 , and R4 is other than H or at least one of Yj, Y 2 , Y 3 , and Y 4 is other than O, or, (2) that where Xi and X 2 are both O, Q is a valence bond, Zi and Z 2 are both -CO 2 H, all of Ri, R , R 3 , and I ⁇ are H, and all of Yi, Y 2 , Y 3 , and Y 4 are O, the compound is the D-(+) enantiomer.
  • compositions comprising chicoric acid analogues and derivatives.
  • These compositions typically comprise: (1) a chicoric acid analogue or derivative in a quantity sufficient to detectably inhibit at least one reaction of integrase selected from the group consisting of 3 '-processing and strand transfer; and (2) an acceptable carrier.
  • acceptable carriers can include alcohols, e.g., ethyl alcohol, serum proteins, human serum albumin, liposomes, buffers such as phosphates, water, sterile saline or other salts, electrolytes, glycerol, hydroxymethylcellulose, propylene glycol, polyethylene glycol, polyoxyethylenesorbitan, other surface active agents, vegetable oils, and conventional anti-bacterial or anti-fungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • An acceptable carrier within the scope of the present invention meets industry standards for sterility, isotonicity, stability, and non- pyrogenicity.
  • the composition can also be in capsule, tablet, or lozenge form as is known in the art, and can include excipients or other ingredients for greater stability or acceptability.
  • the excipients can be inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc, along with the chicoric acid analogue or derivative and other ingredients.
  • compositions are the novel chicoric acid analogues and derivatives described above. These compounds are those of formula (I) where:
  • Q is a valence bond or CH ;
  • X is O, NH, or CH 2 ;
  • X 2 is O, NH, or CH 2 ;
  • Yi, Y 2 , Y 3 , and Y 4 are each a valence bond, O, or NH; where Yi, Y 2 , Y 3 , or Y 4 is a valence bond, the element Ri, R 2 , R 3 , or R bonded to
  • Yi, Y 2 , Y 3 , or Y 4 is a carboxy-containing moiety selected from the group consisting of carboxymethyl, carboxyethyl, carboxypropyl, carboxy small alkyl and carboxy aryl; where Yi, Y 2 , Y 3 , or Y 4 is O, the element Ri, R 2 , R 3 , or R 4 bonded to Yj, Y 2 , Y3, or
  • Y 4 is each H, acetyl, propionyl, butyryl, or isobutyryl, or is a moiety forming a lower alkyl carbamate, or an aryl carbamate; where Yj, Y 2 , Y 3 , or Y 4 is NH, the element R ls R 2 , R 3 , or R 4 bonded to Y ⁇ , Y 2 , Y 3 , or Y is each acetyl, propionyl, butyryl, isobutyryl, small alkyl or aryl; Zi and Z 2 are each H, lower alkyl, -CHO, -CO 2 H, or -CO 2 W, where W is lower alkyl or aryl, or, alternatively, where Q is a valence bond, Zi and Z , together with the adjacent carbon atoms and Q, form a ring structure, the carbon skeleton of the ring structure being selected from the group consisting of cyclohexane,
  • Z 2 are both -CO 2 H, either at least one of Rj, R 2 , R 3 , and R-j is other than H or at least one of Yi, Y 2 , Y , and Y 4 is other than O.
  • L-(-)-chicoric acid (formula D) and D-(+)-chicoric acid (formula 4) were prepared from di-tert-butyl esters of L-(+)-tartaric acid and D-(-)-tartaric acid respectively, using 3,4-diacetylcaffeoyl acid chloride (formula 5) as previously reported. Zhao et al., "Facile synthesis of (2R,3R)-(-)-and (2S,3S)-(+)-chicoric acids," Synthetic Commun. 28, 737-740 (1998).
  • Monocarboxy analogues of formulas 18 - 29 were prepared in a similar, but slightly altered fashion (Scheme 2).
  • Central linkers were first esterified as their methyl esters (refluxing methanolic HCI), then acylated with either diacetylcaffeoyl chloride (formula 5) in pyridine (for formulas 18, 19 - 21) or with diacetylcaffeic acid via hydroxybenzotriazole (HOBt) mixed anhydride coupling (for formulas 22 and 23).
  • Elemental analyses were obtained from Atlantic Microlab Inc., Norcross, GA, and are within 0.4% of the theoretical values unless otherwise indicated.
  • FABMS Fast atom bombardment mass spectra
  • ⁇ NMR data were obtained on a Bruker AC250 spectrometer (250 MHz) and are reported in ppm relative to TMS and referenced to the solvent in which they were run.
  • Anhydrous solvents were obtained commercially and used without further drying. Flash column chromatography was performed using E. Merck silica gel 60 (particle size, 230-400 mesh).
  • HPLC was done on a Waters PrepLC 4000 System using Vydac C18 peptide/protein analytical column. Optical rotation was taken on a Perkin-Elmer 241 digital polarimeter at ambient temperature.
  • N,O-Bis-(3,4-diacetoxycinnamoyl)-2-hydroxyethylamine (formula 12). Reaction of 2-hydroxyethylamine as described above provided formula 12 as a solid (96% yield); mp 177-179.5°C (EtOAc-hexane).
  • (+)-(2S,3S)-O,O-Bis-(3,4-dihydroxycinnamoyl)-2,3-butanediol (formula 13).
  • Treatment of the diester of formula 8 as described above and purification by HPLC (linear gradient, MeOH in H 2 O from 0% to 100% MeOH over 30 min) provided formula 13 as a white solid (73% yield), [ ⁇ ] 20 D + 98° (MeOH, c 0.
  • (+)-(l S,2S)-O,O-Bis-(3,4-dihydroxycinnamoyl)-l ,2- cyclohexanediol (formula 14).
  • Methyl O,O-bis-(3,4-diacetoxycinnamoyI)-2,3- dihydroxypropanoate (formula 18).
  • 2,3-dihydroxypropanoic acid methyl ester (5.0 mmol) in anhydrous pyridine (20 mL) was added a solution of 3,4- diacetyl caffeoyl acid chloride formula 5 (12.5 mmol) in toluene (30 mL) and the resulting cloudy solution was stirred at room temperature overnight.
  • Methyl N,O-bis-(3,4-diacetoxycinnamoyl)serinate (formula 19).
  • Methyl N,N-bis-(3,4-diacetoxycinnamoyl)-2,3-diaminopropanoate (formula 22).
  • N-methylmorpholine 52.1 mmol
  • methyl 2,3- diaminopropanoate dihydrochloride 5.23 mmol
  • 3,4-diacetoxycinnamic acid 10.5 mmol
  • 1 -hydroxybenzotriazole hydrate (10.5 mmol) in CH 2 C1 2 (30 mL) was added diisopropylcarbodiimide (13.60 mmol).
  • N,N-Bis-(3,4-diacetoxycinnamoyl)-2,3-diaminopropanoic acid (formula 25).
  • Treatment of methyl ester formula 22 as described above in the general procedure provided formula 25 as a white solid (67% yield); mp 120°C (dec).
  • N,O-Bis-(3,4.dihydroxycinnamoyl)serine (formula 28).
  • oligonucleotides AE117 (5 ' - ACTGCTAGAGATTTTCCACAC - 3 ' ) (SEQ ID NO: 1) and AE118 (5' - GTGTGGAAAATCTCTAGCAGT - 3') (SEQ ID NO: 2) were purchased from Midland Certified Reagent Company (Midland, TX).
  • the expression vector for the wild-type integrase was a generous gift of T. Jenkins and R. Craigie, Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD.
  • AE118 was 5' -end labeled with T 4 polynucleotide kinase (Gibco BRL, Gaithersburg, Md.) and [ ⁇ -
  • Integrase assays The detailed in vitro assays used to study integrase inhibitors were recently described elsewhere. Mazumder et al., The Humana Press, Inc., Totowa, NJ (1997) (In press). In brief, integrase was preincubated at a final concentration of 200 nM with the inhibitor in reaction buffer (50 mM NaCl, 1 mM HEPES (pH 7.5), 50 ⁇ M EDTA, 50 ⁇ M dithiothreitol, 10% glycerol (wt/vol), 7.5 mM MnCl 2 , 0.1 mg of bovine serum albumin per ml, 10 nM 2-mercaptoethanol, 10% dimethyl sulfoxide (DMSO), and 25 mM MOPS (morpholinepropanesulfonic acid) (pH 7.2)) at 30°C for 30 minutes.
  • reaction buffer 50 mM NaCl, 1 mM HEPES (pH 7.5), 50 ⁇ M
  • % inhibition 100 x [1 -(D-C)/(N-C)], where C, N, and D are the fractions of 21- mer substrate converted to 19-mer (3 '-processing product) or strand transfer products for DNA alone, DNA plus integrase, and integrase plus drug, respectively.
  • IC 50 50% inhibitory concentrations
  • XTT cytoprotection assay Testing performed at the NCI AIDS Drug Screening Laboratory is based on a protocol described by Weislow et al. Weislow et al., "New soluble-formazan assay for HIV-1 cytopathic effects: application to high- flux screening of synthetic and natural products for AIDS antiviral activity," J. Natl. Cancer Inst., 81, 577-586 (1989). In brief, all compounds were dissolved in DMSO and diluted 1 :100 in cell culture medium. Exponentially growing T4 lymphocytes (CEM-SS cell line) were added at 5,000 cells per well.
  • CEM-SS cell line Exponentially growing T4 lymphocytes
  • Frozen virus stock solutions were thawed immediately before use, suspended in complete medium to yield the desired multiplicity of infection, and added to the microtiter wells, resulting in a 1:200 final dilution of the compound.
  • Uninfected cells with the compound served as a toxicity control, and infected and uninfected cells without the compound served as basic controls. Cultures were incubated at 37°C in a 5% CO 2 atmosphere for 6 days.
  • the (2,3-bis-[methoxy-4-nitro-5- sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt (XTT) was added to all wells, and cultures were incubated to allow formazan color development by viable cells.
  • ISIS 5320 NSC 665353
  • ISIS 5320 G quartet- forming ohgonucleotide
  • Retroviruses 10, 1497-1506 (1994)
  • DIBA-1 NSC 654077
  • a NCp7 Zn finger inhibitor a NCp7 Zn finger inhibitor
  • CEM-SS cells were pre-incubated for 15 to 30 min with various concentrations of test compounds.
  • Serial dilutions of HIV-1 ⁇ were added and virus adsorption carried out for 2 h. After 2 h media containing unabsorbed virus was removed and cultures were continued with the appropriate concentrations of compounds in media consisting of RPMI 1640, 10% FCs, 20 ⁇ g/mL gentamicin with 200 mM L-glutamate.
  • HIV-1 N stock was pre-incubated with 100 ⁇ M chicoric acid analog, DIBA-1 (a virucidal nucleocapsid zinc finger inhibitor) or 10 ⁇ M AZT (reverse transcriptase inhibitor) for 90 minutes at 37°C.
  • compound was removed by centrifugation (18,000 x g), lh at 4°C, and the virus pellet re-suspended in RPMI 1640, 10% FCS, 20 ⁇ g/mL gentamicin-200 mM L- glutamate with or without supplemental compound.
  • Virus was serially diluted onto CEM-SS cells (5000 cells/well), adsorbed for 2 h and cultures continued for 6 days with or without supplemental compound.
  • Cell-free supernatants were collected for measurement of HIV-1 p24 by ELISA, and cell viability determined by the XTT dye reduction method. All calculations were corrected for residual p24 from the infection protocol. Results are shown in Table 4.
  • Latently infected tumor necrosis factor ⁇ (TNF- ⁇ ) inducible UI cells were used to determine the effects of the compounds on late phase virus replication as previously described.
  • Turpin et al. "Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of Gag precursors and result in the release of noninfectious virus particles," J. Virol. 70, 6180-6189 (1996).
  • UI cells (5 x 10 4 per 0.2 cm well) were simultaneously treated with 5 ng/mL TNF ⁇ and test compound. Cultures were continued for 48 hours after which cell viability was determined by XTT dye reduction, and cell-free supernatants collected for determination of p24 by the
  • HIV-1 reverse transcriptase (a kind gift from S. Hughes ABL Basic Research NCI-
  • Catechol-containing bis-aryl moieties are a significant structural component in many potent HIV integrase inhibitors. Frequently such compounds are characterized by two aryl units (at least one of which bears 1,2-bis- hydroxylation) separated by a central linker. Zhao et al., J. Med. Chem., supra. Although such analogues exhibit good inhibition against isolated HIV integrase, often corresponding protective effects in HIV-infected cells are not observed (Mazumder et al., Biochemistry, supra; Mazumder et al., J. Med. Chem., supra), perhaps at least partially as a result of limiting collateral cytotoxicity.
  • L-chicoric acid (formula D) exhibits both potent integrase inhibition in isolated enzyme preparations and provides protective effects in HIV-infected cells is therefore worthy of note, since its structure falls within the parameters of prior analogues which lack antiviral activity due to cellular toxicity.
  • One striking feature of L-chicoric acid is the presence of chiral centers in the central linker. Biological systems often discriminate between
  • Tetra-acetate derivatives Tetra-acetate derivatives.
  • the catechol moiety has proven critical for potent integrase inhibition over a wide range of inhibitor subclasses. This has been particularly true for those analogues which can be loosely grouped as "CAPE variants". Since the catechol structure could potentially contribute to unwanted collateral cytotoxicity (Stanwell et al., supra), it would be desirable to eliminate such functionality while maintaining integrase inhibitory potency. Recent efforts in this regard have largely been unsuccessful when applied to CAPE-type inhibitors. Burke et al., supra; Zhao et al., J. Med. Chem., supra.
  • Monocarboxylic analogues The parent chicoric acids are characterized by the presence of two carboxylic acid groups on their central linkers. As exemplified by the dicaffeoylquinic acids however, it has been shown that single carboxyls on a central linker between two caffeoyl esters can provide potent integrase inhibition. Robinson et al., Proc. Natl. Acad. Sci. USA, supra; McDougall et al., supra; Robinson et al., Mol. Pharmacol., supra; King et al., supra. Therefore, it was of interest to examine what effect removal of one carboxylic group from the chicoric acid structures would yield.
  • tetra-acetate formula 25 was incubated under the same conditions as those employed for the integrase assay. Using HPLC analysis, it was observed that formula 25 was stable during the time course of the assay, indicating that the chemical hydrolysis did not occur, and that enzyme inhibition was due to the tetra-acetate itself and not hydrolysis products.
  • Formulas 4 and 7 were reassessed for antiviral activity under more rigorous conditions to determine if our failure to demonstrate antiviral activity as previously reported (Robinson et al., Proc. Natl. Acad. Sci. USA, supra) was an artifact of our detection system.
  • the role of multiplicity of infection (MOI) in the efficacy of these compounds was determined first (Table 3). CEM-SS cells were pretreated for 30 minutes with various doses of formulas 4 and 7 after which the cells were infected with serial dilutions of HIV-1 RF. Cultures were continued in media supplemented with compound for 3, 6 and 9 days, after which supernatants were collected and p24 antigen content measured by ELISA.
  • DIBA-1 (Rice et al, Science, supra)
  • a directly viricidal NCp7 Zn finger reactive compound also resulted in >95% inhibition of virus replication at 1:333 and 1:1000.
  • L-chicoric acid (formula D) and the quinic acids have emerged as interesting classed of caffeoyl-containing catechols exhibiting potent HIV integrase inhibition.
  • These analogues fall within the general category of inhibitors categorized by two aryl groups separated via a central linker, with at least one of the aryl groups being a catechol. While there are a large number of inhibitors within this general class, the multiple reports of anti-HIV activity of L-chicoric acid and quinic acids in cell-based assays has placed them apart from other catechols, which frequently exhibit limiting cytotoxicity. The present study was undertaken to examine features of L-chicoric acid that contribute both to its integrase enzyme inhibition and cell- based activity.
  • L-chicoric acid potentially important for biological efficacy included: (1) Chirality; only the L- enantiomer had been examined for inhibitory potency, (2) Carboxylic acids; the presence of two carboxylic acids on a central linker, (3) Ester linkages; attachment of two caffeoyl groups by ester bonds, (4) Catechols; the presence of two catechol rings.
  • chicoric acid-type compounds While such analysis of chicoric acid-type compounds have identified specific structure-function relationships between these molecules and their ability to inhibit purified integrase, examination of their antiviral activity revealed only very modest inhibitory activity under highly specific conditions.
  • the XTT cytoprotection assay is a well established standardized procedure for determining antiviral activity of unknown compounds. The failure of an unknown to mediate antiviral activity may be due to a number of factors. For the purpose of discussion these factors can be divided into intrinsic (assay determined) and extrinsic (assay independent) assay factors.
  • Compounds may fail in the XTT cytoprotection assay due to intrinsic assay factors such as the multiplicity of infection (MOI, ratio of virus particles to target cell) and the timing of compound addition in relation to the infection event. These two parameters were investigated in detail (Tables 3-4). Antiviral activity was found to be MOI dependent, requiring preincubation of the virus and chicoric acid analogue followed by subsequent culture in compound-containing media to elicit maximal antiviral activity. Even with optimal MOI's and continuous exposure to the chicoric acid analogues, antiviral activity was far less potent than that mediated by either AZT or DIBA-1. Furthermore under optimized conditions inhibition was transient.
  • MOI multiplicity of infection
  • DIBA-1 the timing of compound addition in relation to the infection event.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des dérivés et analogues d'acide chicorique qui exercent une activité contre l'intégrase du VIH 1. Les caractéristiques structurelles qui sont nécessaires à cette activité sont élucidées en dosant ces analogues et dérivés contre l'intégrase du VIH 1. En outre, l'invention porte sur des méthodes de synthèse des énantiomères d'acide chicorique même, ainsi que de ses analogues et dérivés. Par ailleurs, elle concerne des méthodes d'utilisation des dérivés et analogues d'acide chicorique afin d'inhiber l'intégrase du VIH 1, ainsi que des compositions comprenant lesdits dérivés et analogues.
PCT/US2000/004608 1999-02-22 2000-02-22 Analogues acetyles et correspondants d'acide chicorique en tant qu'inhibiteurs de l'integrase du vih WO2000063152A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1671535A1 (fr) 2004-12-16 2006-06-21 Stiftung Caesar Center of Advanced European Studies and Research Procédés de modification des concentrations en composés phénoliques dans des cellules végétales
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
WO2015124846A1 (fr) 2014-02-19 2015-08-27 Institut National De La Recherche Agronomique - Inra Composition phytosanitaire
US9284323B2 (en) 2012-01-04 2016-03-15 Gilead Sciences, Inc. Naphthalene acetic acid derivatives against HIV infection
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
CN113845422A (zh) * 2021-11-04 2021-12-28 山东中医药大学 一种从紫锥菊中批量制备高纯度l-菊苣酸的工艺及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999048371A1 (fr) * 1998-03-27 1999-09-30 The Regents Of The University Of California Nouveaux inhibiteurs de vih integrase et traitement du vih fonde sur des combinaisons de medicaments contenant des inhibiteurs d'integrase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999048371A1 (fr) * 1998-03-27 1999-09-30 The Regents Of The University Of California Nouveaux inhibiteurs de vih integrase et traitement du vih fonde sur des combinaisons de medicaments contenant des inhibiteurs d'integrase

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 127, no. 13, 29 September 1997, Columbus, Ohio, US; abstract no. 173872, BUDZIANOWSKI, JAROMIR: "Coumarins, caffeoyltartaric acids, and their artifactual methyl esters from Taraxacum officinale leaves" XP000916756 *
HE ZHAO: "Facile synthesis of ...", SYNTHETIC COMMUN, vol. 28, no. 4, - 1998, pages 737 - 740, XP000916763 *
KAI ZHU ET AL.: "Irreversible Inhibition ...", JOURNAL OF VIROLOGY, 1 April 1999 (1999-04-01), pages 3309 - 3316, XP000916737 *
KING ET AL.: "Structure-Activity Relationship ...", J MED CHEM, vol. 42, - 27 January 1999 (1999-01-27), pages 497 - 509, XP000919203 *
LIN ET AL.: "Chicoric Acid Analogues as HIV-1 Integrase Inhibitors", J. MED. CHEM., vol. 42, 4 June 1999 (1999-06-04), pages 1401 - 1414, XP000919180 *
PLANTA MED. (1997), 63(3), 288, XP000916756 *
ROBINSON ET AL.: "Dicaffeoylquinic acid inhibitors ...", MOL PHARMACOL, vol. 50, no. 4, - 1996, pages 846 - 855, XP000916694 *
ROBINSON ET AL.: "Inhibitors of HIV-1 replication ...", PROC NATL ACAD SCI USA, vol. 93, - 1996, pages 6326 - 6331, XP000919204 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1671535A1 (fr) 2004-12-16 2006-06-21 Stiftung Caesar Center of Advanced European Studies and Research Procédés de modification des concentrations en composés phénoliques dans des cellules végétales
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
US9284323B2 (en) 2012-01-04 2016-03-15 Gilead Sciences, Inc. Naphthalene acetic acid derivatives against HIV infection
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
US9096586B2 (en) 2012-04-20 2015-08-04 Gilead Sciences, Inc. Therapeutic compounds
WO2015124846A1 (fr) 2014-02-19 2015-08-27 Institut National De La Recherche Agronomique - Inra Composition phytosanitaire
US9820485B2 (en) 2014-02-19 2017-11-21 Institut National De La Recherche Agronomique-Inra Phytosanitary composition
CN113845422A (zh) * 2021-11-04 2021-12-28 山东中医药大学 一种从紫锥菊中批量制备高纯度l-菊苣酸的工艺及应用
CN113845422B (zh) * 2021-11-04 2024-01-30 山东中医药大学 一种从紫锥菊中批量制备l-菊苣酸的工艺及应用

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