Uvaria

Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer’s disease. As a springboard to explore new anti-cancer and anti-Alzheimer’s chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species Uvaria alba using in vitro assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of U. alba elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profil...

Endophytic fungi are less explored in terms of their pharmacological applications, thus screening their phytochemical constituents and biological activities is of interest. In this study, the endophytic fungi Nigrospora and Colletotrichum spp. were isolated from the leaves of Uvaria grandiflora. The identity of the endophytes was established by molecular analysis of their fungal intergenic spacer. Biological screening showed that the fungal endophytes were most active against methicillin-resistant Staphylococcus aureus (MRSA), with the ethyl acetate broth extract of Colletotrichum sp. showing the biggest zone of inhibition (ZOI) for MRSA at 19 mm. For antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, the ethyl acetate broth extract of Nigrospora sp. elicited better antibacterial activity (ZOI > 11 mm). Antioxidant assessment using 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and superoxide scavenging assays showed that Nigrospora broth extract had the best free radical scavenging activity with an IC 50 of 3.92 mg/mL. Meanwhile, the broth extract from Colletotrichum sp. showed the best reducing power (RP 50 = 4.41 mg/mL) and superoxide scavenging activity (SC 50 = 0.78 mg/mL). Using Artermia salina for toxicity screening, both fungi were toxic having an LD 50 < 0.40 mg/mL. The culture broth extracts showed greater antibacterial, antioxidant, and cytotoxic activities compared to the mycelial extracts. Phytochemical screening of the broth extract revealed the presence of flavonoids, sterols, phenols, and terpenoids in both fungal extracts. Tannins and coumarins were specifically detected in Colletotrichum sp., while alkaloids and indole derivatives were detected only in the Nigrospora endophyte.

Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer’s disease. As a springboard to explore new anti-cancer and anti-Alzheimer’s chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species Uvaria alba using in vitro assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of U. alba elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profil...

Four dimeric chalcone derivatives, 8″,9″-dihydrowelwitschin H, uvarins A-C, a naphthalene derivative, 2-hydroxy-3-methoxy-6-(4&amp;#39;- hydroxyphenyl)naphthalene, and the known dimeric chalcones, dependensin and welwitschin E, flavonoids, a cyclohexane oxide derivative, an aromatic aldehyde were isolated from the roots of Uvaria siamensis (Annonaceae). The structures of the compounds were elucidated by spectroscopic analysis, as well as by comparison with literature data. The isolated compounds with a sufficient amount for biological assays were evaluated for their antimalarial, antimycobacterial, and cytotoxic activities. The dimeric chalcones 8″,9″-dihydrowelwitschin H, uvarins B and C, dependensin and welwitschin E showed strong antiplasmodial activity with IC values of 3.10, 3.02, 3.09, 4.21 and 3.99 μg/mL, respectively. A possible biosynthesis pathway of the dimeric chalcones is discussed.

1The Graduate School 2Faculty of Medicine and Surgery 3Department of Biochemistry, Faculty of Pharmacy 4Laboratory for Organic Reactivity, Discovery, and Synthesis, Research Center for the Natural and Applied Sciences (RCNAS) University of Santo Tomas (UST), España 1015 Manila, Philippines 5South China Botanical Garden, Guangzhou, Guangdong 510650 China §These authors contributed equally to this paper

Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer’s disease. As a springboard to explore new anti-cancer and anti-Alzheimer’s chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species Uvaria alba using in vitro assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of U. alba elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profiling analysis of the bioactive extract identified 18 putative secondary metabolites. Molecular docking and molecular dynamics simulations showed strong free energy binding mechanisms and dynamic stability at 50-ns simulations in the catalytic domains of PDE4 B2B, ubiquitin-specific peptidase 14, and Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) for the benzylated dihydroflavone dichamanetin (16), and of an AChE and KEAP-1 BTB domain for 3-(3,4-dihydroxybenzyl)-3′,4′,6-trihydroxy-2,4-dimethoxychalcone (8) and grandifloracin (15), respectively. Density functional theory calculations to demonstrate Michael addition reaction of the most electrophilic metabolite and kinetically stable grandifloracin (15) with Cys151 of the KEAP-1 BTB domain illustrated favorable formation of a β-addition adduct. The top-ranked compounds also conferred favorable in silico pharmacokinetic properties.