THE CHEMICAL AND BIOLOGICAL ROLE OF PIMARANES

AND LABDANES FROM MEXICAN SALVIA SPECIES

Nancy Ortiz-Mendozaa,b, María Eva González-Trujanoc*, Martha J. Martínez-Gordillod,

Itzi Fragoso-Martíneze, Francisco A. Basurto-Peñaf, Iván J. Bazany Rodríguezg,
Alejandro Dorazco-Gonzálezg, Eva Aguirre-Hernándezb*

ABSTRACT

The genus Salvia (Lamiaceae) is widely distributed in Mexico with approximately

300 species. Aerial parts, leaves, and branches of sages are prepared as infusions
or decoctions in traditional Mexican medicine to treat conditions such as dysentery,
diarrhea, gastritis, stomach-ache, headache, sore throat, cough, bronchitis, fever,
diabetes, epilepsy, nerves, insomnia, anxiety, among other ailments. The aim of this
review was to compile and resume relevant information from literature regarding
the chemical constituents of the pimarane and labdane type isolated from Mexi-
can Salvias and their biological activities covering the period from 1986 to 2022.
A total of 31 compounds of these types were registered with 24 pimaranes and 7
labdanes. It was noticed that scientific evidence of the participation in the medicinal
effects of Salvia species has not yet been reported for most of these diterpenoids.
However, those described as bioactive have shown antibacterial, anticancer, anti-
inflammatory, antihypotensive, antimutagenic, and antidiabetic properties. The
present review provides information on the chemical and biological properties of
pimaranes and labdanes from Mexican Salvia species suggesting their potential
to become an option of treatment for diabetes and cancer, among other common
diseases of Mexican population and of all the world. Nevertheless, further research
is encouraged to demonstrate the benefits of these chemical constituents for health.
Key words: Bioactive compound, Labdanes, Pimaranes, Diterpenes, Lamiaceae,
Salvia

a
Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, México.
b
Laboratorio de Productos Naturales, Departamento de Ecología y Recursos Naturales, Facultad de Ciencias,
Universidad Nacional Autónoma de México, Ciudad de México, México.
c
Laboratorio de Neurofarmacología de Productos Naturales, Dirección de Investigaciones en Neurociencias
del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, México.
d
Herbario de la Facultad de Ciencias, Departamento de Biología Comparada, Facultad de Ciencias, Univer-
sidad Nacional Autónoma de México, Ciudad de México, México.
e
Flora de Veracruz, Secretaría Académica, Instituto de Ecología, A.C., Xalapa, México.
f
Jardín Botánico, Instituto de Biología, Universidad Nacional Autónoma de México, Ciudad Universitaria,
Ciudad de México, México.
g
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad de México, México.
*Corresponding authors: b +52 55 10167382. eva_aguirre@ciencias.unam.mx, c+52 55 41605084. evagon-
tru@yahoo.com.mx

23
24 Ortiz-Mendoza, N., et al.

RESUMEN

El género Salvia (Lamiaceae) está ampliamente distribuido en México con aproxima-

damente 300 especies. Las partes aéreas, hojas y ramas de salvias son preparadas
como infusiones o decocciones y se utilizan en la medicina tradicional mexicana
para tratar padecimientos como disentería, diarrea, gastritis, dolor de estómago,
dolor de cabeza, dolor de garganta, tos, bronquitis, fiebre, diabetes, epilepsia, ner-
vios, insomnio, ansiedad, entre otras enfermedades. El objetivo de esta revisión
fue compilar y resumir información de la literatura acerca de los constituyentes
químicos de tipo pimarano y labdano aislados de salvias mexicanas cubriendo el
periodo de 1986 a 2022, incluyendo aquellas con actividad biológica. Un total de
31 compuestos de este tipo fueron registrados como 24 pimaranos y 7 labdanos. La
evidencia de la participación de estos diterpenoides en los efectos medicinales de las
especies de Salvia aún no ha sido reportada para la mayoría de estos metabolitos.
Sin embargo, los que se han descrito como bioactivos demostraron presentar pro-
piedades antibacterianas, anticancerígenas, antiinflamatorias, antihipotensivas,
antimutagénicas y antidiabéticas. La presente revisión proporciona información
sobre la importancia química y biológica de los pimaranos y labdanos de salvias
mexicanas sugiriendo a estos constituyentes como posibles alternativas para el
tratamiento de la diabetes y el cáncer, entre otras enfermedades que son comunes
en México y en todo el mundo. No obstante, más investigación es requerida para
demostrar los beneficios de estos componentes químicos para la salud.
Palabras clave: Compuestos bioactivos, Labdanos, Pimaranos, Diterpenos, La-
miaceae, Salvia.

Introduction the country (Martínez-Gordillo et al., 2013;

2017). These species mainly belong to the
Mexico is a vast source of ethnobotanical subgenus Calosphace (288 spp.), followed
knowledge, since it encompasses a great by subgenus Audibertia (13 spp.) and clade
diversity of medicinal plant species (ca. Heterosphace (5 spp.). Regarding the diver-
4,000 spp.; Ramamoorthy & Elliot, 1993). sity of salvias in Mexico, the most species-
This diversity has motivated various in- rich states are Oaxaca (98 species), Jalisco
vestigations of herbal medicine with the (91), Guerrero (82), Puebla (79), Michoacán
purpose of endorsing its traditional use. (68) (Martínez-Gordillo et al., 2017). The
However, finding effective and safe molecu- species of this genus are herbs and shrubs
les with pharmacological activity that can that thrive mainly in temperate forests (e.g.,
tackle health problems faced by the world conifer and oak forests and cloud forests),
population remains a challenge. but they can also be found in deciduous
The genus Salvia, from the mint family and sub-deciduous forests and in arid zo-
(Lamiaceae), has around 1,000 species nes (Espejo & Ramamoorthy, 1993).
worldwide (Etminan et al., 2018). These Ethnobotanical studies in Mexico have
species are divided into ten clades, nine reported that in the traditional medicine,
of them currently considered formally as the aerial parts of the sages are prepared
subgenera (Drew et al., 2017). Mexico is as an infusion or decoction to treat ail-
one of the most important centres of di- ments of the gastrointestinal system such
versification of the genus, harbouring ca. as dysentery, diarrhea, bile, gastritis, and
306 species of sages, 75.6% endemic to stomach pain (Domínguez-Vázquez & Cas-
The chemical and biological role of pimaranes and labdanes from mexican Salvia species Rev. Latinoamer. Quím. 50/1(2023) 25

tro-Ramírez, 2002; Jenks & Seung-Chul, this review were verified following the chec-
2013; De La Cruz-Jiménez et al., 2014; klists of Martínez-Gordillo et al., (2017)
Ortiz-Mendoza et al., 2022). Additionally, and González-Gallegos et al., (2020). The
the infusions are also used to relieve ear, ethnopharmacology and phytochemistry
head, and throat pain. Regarding the cen- studies were searched in scientific data-
tral nervous system, the decoctions have bases of several platforms and editorials
been reported to be useful against epilepsy, such as Google, Google Scholar, PubMed,
“nervios’’ or anxiety and insomnia (Jenks & Elsevier, Science Direct, Springer, Willey,
Seung-Chul, 2013; Casselman et al., 2014), Taylor & Francis, ACS, and RSC, using
fever and other conditions such as cough keywords like Salvia and more specific
and bronchitis (Ortiz-Mendoza et al., 2022). terms such as epithets (e.g., Salvia ade-
Phytochemical and pharmacological nophora, S. semiatrata, S. urica, etc.). This
studies to identify, characterise, and isolate review includes literature from 1986 to
the compounds responsible for the biologi- 2022. All the literature found in databases
cal activity of various species of Salvia have was classified, systematised, organised,
allowed to recognize several molecules that and finally summarised in Table 1. To
belong to document chemical groups such avoid duplication of information regarding
as monoterpenes, sesquiterpenes, diterpe- the use of names other than chemical
nes, triterpenes and phenolic compounds compounds, the digital databases of the
(Ortiz-Mendoza et al., 2022). Although in National Institute of Standards and Tech-
this genus the diterpenes with abietane nology (NIST), of the National Center for
and clerodane-type skeleton structures Biotechnology Information (NCBI) were
have been highlighted for being the most used, which allowed us to verify synonyms
abundant and diverse of the identified in chemical nomenclature or the trivial
compounds (Rodríguez-Hahn, et al., 1995, names of molecules.
Jenks & Seung-Chul, 2013; Esquivel, 2008;
Esquivel et al, 2017; Fragoso-Serrano et Chemical compounds isolated as pimarane or
al., 2019), other constituents that are less labdane from Salvia species
abundant (e.g., pimaranes and labdanes) Terpenes are ubiquitous natural pro-
are also important, because their presence ducts generated by two well-established
allows characterization of these species as biosynthetic pathways: the mevalonate
well. Pimaranes are tricycle diterpenes with pathway and the more recently discovered
different stereochemistry features and are 1-deoxyxylulose-5-phosphate pathway
biosynthetically related to labdane terpe- (Reveglia et al., 2018). Of the variety of
noids (Isca et al., 2020). The phytochemical compounds that have been isolated and
and biological evaluation, and the impact characterised in species of the genus Sal-
on health benefits of these constituents via, most of the diterpenes that have been
are not yet described. This review focuses described belong to species of subgenus
on compiling and integrating scientific Calosphace (Ortiz-Mendoza et al., 2022).
information of the studies focused on the Among the nature of the different chemi-
phytochemical and biological activity of the cal groups identified in Mexican species
groups of pimaranes and labdanes in spe- of Calosphace, ca. 450 compounds have
cies of Salvia, which will allow to recognize been characterised. According to their
their existing contributions and to promote structures, these compounds are classi-
their research, identification, isolation and fied into four main subgroups (i.e., mono-,
biological characterization. di-, sesqui- and triterpenoids). However,
The Mexican species of subgenera Au- the pimaranes and labdanes are the least
dibertia and Calosphace considered for abundant of all the diterpenoids (Fig. 1).
26 Ortiz-Mendoza, N., et al.

Figure 1. Secondary metabolites in Mexican species of Salvia specifying the number of

constituents that have been characterised per group.

Only nine species of Mexican sages have It is worth noting that eight of these spe-
been reported to synthesise labdanes (LB) cies, all belonging to subgenus Calospha-
and pimaranes (PM). Eight of these species ce, are widely distributed (S. cinnabarina,
belong to subgenus Calosphace and one to S. elegans, S. leucantha, S. tiliifolia, S.
subgenus Audibertia, and they are integra- mexicana, S. hispanica, S. coccinea and S.
ted in this review as 24 PM (7%) and 7 LB microphylla) and therefore inhabit different
(2%) as follows: S. cinnabarina (4 LB & 3 microenvironments. Additionally, three of
PM), S. elegans (1 LB & 3 PM), S. dugesii (1 them share both types of diterpenes, su-
LB & 2 PM), S. parryi (7 PM), S. microphylla ggesting that greater diversity of metaboli-
(5 PM), S. greggii (4 PM), S. leucantha (1 LB tes can contribute to their ability to adapt to
& 1 PM), S. mellifera (2 PM), S. fulgens (1 different ecological conditions and increase
PM) (Table 1, Figure 2). It is important to their dispersal ability.
mention that four pimaranes are found in
more than one Salvia species.

Figure 2. Chemical structure describing the pimaranes and labdane-type skeletons and
derivatives found in Mexican species of Salvia.
The chemical and biological role of pimaranes and labdanes from mexican Salvia species Rev. Latinoamer. Quím. 50/1(2023) 27

Figure 2. Chemical structure describing the pimaranes and labdane-type skeletons and
derivatives found in Mexican species of Salvia (Continuation).
28 Ortiz-Mendoza, N., et al.

BIOLOGICAL ACTIVITIES Salvia cinnabarina (subgenus Calospha-

ce) is one of the most studied species, and
Pimaranes and labdane-type diterpenes pimaranes and labdane-type constituents
found in Mexican sages have been scarcely have been isolated from it. This species is
explored for biological activity. However, recognized as a medicinal plant in Chiapas
these kinds of metabolites have been iden- and Oaxaca, where it is used for pain relief
tified and explored for their biological acti- in rheumatism as an antispasmodic (Ortiz-
vities in other plant species (see Table 1). Mendoza et al., 2022). From this species,
The pimarane, isopimarane, and ent- the leaf exudate of populations collected in
pimarane-type diterpenes are associated Puebla was investigated, leading to the iso-
to a wide range of biological activities in- lation of a 3,4-seco-isopimarane diterpenoid
cluding antimicrobial, antifungal, antiviral, whose structure and relative stereochemis-
cytotoxicity, antispasmodic and relaxant try was established as 3,4-seco-isopimara-
effects (Reveglia et al., 2018). Similarly, the 4(18),7,15-trien-3-oic acid as possible res-
labdane-type diterpenes possess biological ponsible of the antispasmodic in in vitro as-
activities such as antibacterial, antifun- says (Romussi et al., 2001). This compound
gal, antiprotozoal, enzyme inducing, anti- has also been identified in S. elegans, which
inflammatory activities and modulation is closely related to S. cinnabarina (Martínez-
of immune cell functions, in cancer and Gordillo et al., 2013; Fragoso-Martínez et
in cardiovascular disorders (Singh et al., al., 2018). In addition, two new labdane-
1999). type diterpenoids—malonylcommunol and
Pimaranes are tricycle diterpenes with 6β-hydroxy-trans-communic acid—were
different stereochemistry features and are evaluated in yeast α-glucosidases to de-
biosynthetically related to labdane terpe- monstrate a concentration-dependent
noids (Isca et al., 2020). The presence of inhibition together to two already known
both types has been identified in Mexican labdane diterpenoids, trans-communic acid
species of Salvia, being the pimaranes and trans-communol (Bustos-Brito et al.,
more representative than labdanes, since 2020). Antimutagenic activity was repor-
24 molecules were found in contrast to 7 ted for a pimarane diterpene isolated from
cases, respectively. this species and named 3,4-secoisopimar-
The diversity of terpenoid compounds 4(18),7,15-trien-3-oic acid. It is suggested
produced by plants plays an important that the antimutagenic mechanism of action
role in mediating various plant-herbivore, of this compound is through the alteration of
plant-pollinator, and plant-pathogen cell permeability, which blocks the mutagen
interactions, where a single amino acid adsorption across the bacterial membrane,
mutation can switch levopimaradiene/ or by chemical or enzymatic inhibition of
abietadiene synthase to produce isopima- the mutagens (Di Sotto et al., 2009). Dose-
radiene or sandaracopimaradiene (Keeling response hypotensive action was reported
et al., 2008). Derivatives found in the spe- for the natural diterpene 3,4-seicosopimar-
cies of Salvia so far lack scientific evidence 4(18),7,15-triene-3-oic acid isolated from S.
on their biological activity are included in cinnabarina by an independent nitric oxide
Table 1. mechanism of action (Alfieri et al., 2007).
Diterpenoids, especially of the isopima- Whereas NO production was observed
rane type have been reported in specific when this constituent inhibited rat bladder
taxa such as those from the genus Kaem- contractility (Capasso et al., 2004), as well
pferia (Zingiberaceae), which are plants wi- as spasmolytic activity by several neuro-
dely used in traditional medicine worldwide transmission systems mechanisms of action
(Elshamy et al., 2019). (Romussi et al., 2001).
The chemical and biological role of pimaranes and labdanes from mexican Salvia species Rev. Latinoamer. Quím. 50/1(2023) 29

Table 1. Pimaranes and labdane-type diterpenes found in Mexican species of Salvia and their biological
activities
Compound identified Salvia species Biological activity Reference
Pimaranes
1 Isopimaradiene S. mellifera n.d. Luis et al., 1993
2 Isopimara-6,8(14),15- S. parryi n.d. Guajardo et al.,
triene 1997
3 Isopimara-8(14),15-dien- S. parryi n.d. Guajardo et al.,
7-one 1997

4 Isopimara-8,15-dien- S. parryi n.d. Guajardo et al.,

7-one 1997
5 7α-hydroxyisopimara- S. parryi n.d. Guajardo et al.,
8(14),15-diene 1997
6 8(14),15-isopimaradien- S. mellifera n.d. Luis et al., 1993
7α-ol
7 Isopimaric acid S. gregii Activity against Sta- Smith et al., 2005,
phylococcus aureus Tanaka et al.,
multidrug-resistant 2008
(MIC 32-64 µg/mL).
Inhibitory effects
Epstein-Barr virus
(IC50 =352 mol ratio/
TPA)
8 Isopimara-7,15-dien- S. cinnabarina n.d. Bustos-Brito et al.,
3-one 2020
9 Isopimara-7,15-dien-3β-ol S. cinnabarina n.d. Busto-Brito et al.,
2020
10 3β-hydroxy-isopimaric S. gregii n.d. Bruno et al., 1986
acid
11 14α-hydroxyisopimaric acid S. microphylla/S. n.d. Bruno et al., 1986;
gregii Luis et al., 1993
12 14α, 18-dihydroxy-7,15- S. gregii/S. n.d. Bruno et al., 1986;
isopimaradiene microphylla Luis et al., 1993
13 14α-hydroxyisopimara- S. parryi n.d. Guajardo et al.,
7,15-diene 1997
14 Pimaradiene S. leucantha n.d. Upadhyaya et al.,
2013
15 Pimara-7,15-dien-3-one S. elegans n.d. Mathew & Thoppil,
2011
16 Pimara-7,15-dien-3-ol S. elegans n.d. Mathew & Thoppil,
2011
17 Pimaradiene-7α,18-diol S. microphylla n.d. Luis et al., 1993
18 Sandaracopimaradiene S. dugesii/S. Nitric oxide inhibitory Calderón-Oropeza
parryi activity (IC50 =18.6 μM) et al., 2021; Gua-
jardo et al., 1997;
Tungcharoen et
al., 2020
30 Ortiz-Mendoza, N., et al.

Table 1. Continuation

Compound identified Salvia species Biological activity Reference

19 Sandaracopimaric acid S. fulgens Relaxation of pulmo- Gao et al., 2014
nary artery via P13K/
Akt-eNOS
20 7α-hydroxy- S. microphylla n.d. Luis et al., 1993
sandaracopimaric acid
21 7α-acetoxy- S. microphylla n.d. Luis et al., 1993
sandaracopimaric acid
22 3,4-secoisopimar- S. Hypotensive effect (30 Romussi et al.,
4(18),7,15-trien-3-oic acid cinnabarina/S. mg/kg, i.v.), in male 2000; Alfieri et al.,
elegans Wistar rats. Spas- 2007; Di Sotto et
molytic activity on al., 2009
acetylcholine-induced
contractions in the iso-
lated guinea-pig ileum
(IC50= 1.5 µg/mL).
Antimutagenic acti-
vity, Ames ‘test on S.
typhimurium TA98 and
TA100 and on E. coli
(92.2% against 2-ami-
noanthracene).
23 Rimuene S. dugesii n.d. Calderón-Oropeza
et al., 2021
24 Parryin S. parryi n.d. Guajardo et al., 1997
Labdanes
25 Malonylcommunol S. cinnabarina α-glucosidase inhibitor Bustos-Brito et al.,
in yeast (IC50 =20.96 2020
µM)
26 6β-hydroxy-trans-communic S. cinnabarina Anti-inflammatory in Bustos-Brito et al.,
acid edema induced by TPA 2020
(21.72% inhibition at
1.0 µmol/ear). The
α-glucosidase inhibitor in
yeast (IC50 =43.74 µM)
27 Trans-communic acid S. cinnabarina Anti-inflammatory Bustos-Brito et al.,
in edema induced by 2020
TPA (9.09% inhibition
at 1.0 µmol/ear). The
α-glucosidase inhibitor in
yeast (IC50 =45.15 µM)
28 Trans-communol S. cinnabarina n.d. Bustos-Brito et al.,
2020
29 Sclareol oxide S. dugesii n.d. Calderón-Oropeza et
al., 2021
30 Sclareol S. elegans Anti-cancer, anti-inflam- Zhou et al., 2020
matory, anti-hyperten-
sive, and anti-diabetic
effects.
31 Sclarene S. leucantha n.d. Villalta et al., 2021
n.d. no data
The chemical and biological role of pimaranes and labdanes from mexican Salvia species Rev. Latinoamer. Quím. 50/1(2023) 31

Salvia elegans, S. greggii, and S. offici- flavescens, and E. hirae (Isca et al., 2020).
nalis L. prepared as decoction were repor- Labdanes of Vitex negundo L. (Lamiaceae)
ted to possess benefits against metabolic are effective on E. coli and S. aureus strains
diseases because of their α-glucosidase, (Sichaem et al., 2021).
α-amylase, and pancreatic lipase activities, In conclusion, few studies have been
as well as antioxidant properties. However, done by analysing the biological properties
these effects were only associated with of pimarane- and labdane-type diterpenes
possible involvement of phenolic acids (Pe- in Salvias. Although they were found to be
reira et al., 2018). It should be interesting less abundant metabolites of this genus,
to investigate the role of possible labdanes they are also scarcely examined to inves-
and pimaranes found in this species but tigate their value for biological activities.
not yet explored for their biological activity. Nevertheless, scientific evidence found in
Sandaracopimaradiene and rimuene, literature suggests their involvement in
two pimaranes already reported in Kaem- diseases of major importance around the
pferia galanga (Zingiberaceae) describing world. Since according to reports of WHO
anti-inflammatory activity (Tungcharoen in 2022, cardiovascular diseases, diabetes,
et al., 2020) and as a useful treatment and cancer as non-communicable diseases
against polycystic ovary syndrome in Thuja now outnumber infectious diseases as the
occidentalis were identified in S. dugessi “top killers globally”. Therefore, it is of great
(Cupressaceae; Küpeli-Akkol et al., 2015). relevance to look for health alternatives,
No specific activities have been descri- where salvia species might be a source of
bed for pimarane-type diterpenes isolated new drugs for effective and safety therapy.
of S. parryi. However, some of their consti-
tuents in other species have been conside- ACKNOWLEDGMENTS
red to possess antimicrobial activity (Porto
et al., 2009) and vascular relaxation (Hi- This work was supported by the program
pólito et al., 2009). The sclarene identified UNAM-PAPIIT [No. IN221221]. Ortiz-Men-
in S. leucantha has been described among doza thanks Postgraduate in Biological
the constituents in the immunostimulant Sciences at the National Autonomous Uni-
effects of frankincense oil (Mikhaeil et al., versity of Mexico for having received Ph.D.
2003), as well as antibacterial activity iso- academic training and CONACYT fellowship
lated from Nicotiana glutinosa (Solanaceae; number 793655.
Popova et al., 2019). Whereas, the sclareol
characterised in S. elegans has been re- AUTHOR CONTRIBUTIONS
ported to possess antimicrobial but also
proapoptotic activity (Wang et al., 2015). Aguirre-Hernández, Martínez-Gordillo, and
The resistance that microorganisms González-Trujano participated in the con-
have developed against various drugs has ceptualization, investigation, supervision,
led to the search for new sources of anti- and writhing original draft preparation.
microbials and anti-inflammatories, which Ortiz-Mendoza participated in the compi-
also have fewer side effects. Among the lation, systematization, and elaboration
compounds explored are diterpenes of the of the tables to resume information of the
pimarane and labdane type, for example, labdanes and pimaranes in Mexican Salvia
isopimarane isolated from Aeollanthus species. Fragoso-Martínez and Basurto-
rydingianus van Jaarsv & A.E.van Wyk Peña participated in the investigation of
(Lamiaceae) has been tested. This com- literature information. Ortiz-Mendoza,
pound has proven to be effective on strains Dorazco-González, and Bazany-Rodríguez
of S. aureus and E. faecalis, E. faecium, E. contributed with the chemical information
32 Ortiz-Mendoza, N., et al.

of labdanes and pimaranes. All authors

have read and agreed to the final version
of the manuscript. This paper was taken in
part from the Ph.D. of the Student Nancy
Ortiz-Mendoza.

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