Cytotoxic, immunomodulatory, antimycotic, and antiviral activities of semisynthetic 14-hydroxyabietane derivatives and triptoquinone C-4 epimers

Zapata, Bibiana; Rojas, Mauricio; Betancur‐Galvis, Liliana; Mesa-Arango, Ana Cecilia; Pérez-Guaita, David; González, Miguel A.

doi:10.1039/c3md00151b

Cited by 26 publications

(20 citation statements)

References 36 publications

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“…The ready availability of these materials from our studies (4b-5) and the absence of their biological studies as well as chemical manipulation prompted us to carry out this research. Thus, in continuation of our research program to discover bioactive terpenoids [10][11][12][13], we carried out the synthesis of several derivatives of methyl callitrisate (4b), including callitrisic acid (4a), jiadifenoic acid C (5), and 4-epidehydroabietol or callitrisinol (6) together with an evaluation of their antiproliferative and modulating GABA A receptor activities. Herein, the evaluation of compounds 1-6 against a panel of six representative human solid tumor cell lines and their effect on GABA A receptors (α 1 β 2 γ 2s ) are reported.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

Stadler

Padrón

González-Cardenete

2017

PMIO

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The semisynthesis and biological activity of the naturally occurring abietane diterpenoids callitrisic acid (4a; 4-epidehydroabietic acid) and callitrisinol (6) are reported. These compounds and jiadifenoic acid C (5) were obtained from methyl callitrisate (4b) isolated from Sandarac resin for biological evaluation and comparison with the biological activities of C4 epimers such as dehydroabietic acid (2a). In particular, the antiproliferative activity against a panel of six representative human solid tumor cell lines (A549, HBL-100, HeLa, SW1573, T-47D, WiDr) and the effect on GABAA receptors (α 1 β 2 γ 2s) were evaluated. The GI50 values were in the range of 3.4–61 µM and the potentiation of IGABA was 269–311% at 100 µM. Callitrisinol (6) was found to be 6.7-fold more potent than the reference etoposide in the WiDr (colon) cancer cell line. The role of the stereogenic center at C4 for antiproliferative and GABAA receptor modulating activities in the dehydroabietane scaffold has thus been revealed.

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Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

Stadler

Padrón

González-Cardenete

2017

PMIO

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“…1) and the quinone arenarone (compound 13 in Fig. 1), both of which have been reported to have antiinfective or anticancer activity (34)(35)(36)(37)(38)(39). All three terpenoid inhibitors (compounds 11, 12, and 13) thus contain either the hydroxyquinone methide fragment found in the terpenoid celastrol (compound 9) and compound 10 or a quinone moiety (compound 13); all three compounds (11, 12, and 13) are quite active against FPPS (SI Appendix, Table S1) and have been reported to be active against tumor cells (35,40,41).…”

Section: Resultsmentioning

confidence: 99%

Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site

Liu¹,

Lindert

Zhu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We used in silico methods to screen a library of 1,013 compounds for possible binding to the allosteric site in farnesyl diphosphate synthase (FPPS). Two of the 50 predicted hits had activity against either human FPPS (HsFPPS) or Trypanosoma brucei FPPS (TbFPPS), the most active being the quinone methide celastrol (IC 50 versus TbFPPS ∼20 μM). Two rounds of similarity searching and activity testing then resulted in three leads that were active against HsFPPS with IC 50 values in the range of ∼1-3 μM (as compared with ∼0.5 μM for the bisphosphonate inhibitor, zoledronate). The three leads were the quinone methides taxodone and taxodione and the quinone arenarone, compounds with known antibacterial and/or antitumor activity. We then obtained X-ray crystal structures of HsFPPS with taxodione+zoledronate, arenarone+zoledronate, and taxodione alone. In the zoledronate-containing structures, taxodione and arenarone bound solely to the homoallylic (isopentenyl diphosphate, IPP) site, not to the allosteric site, whereas zoledronate bound via Mg 2+ to the same site as seen in other bisphosphonate-containing structures. In the taxodione-alone structure, one taxodione bound to the same site as seen in the taxodione+zoledronate structure, but the second located to a more surface-exposed site. In differential scanning calorimetry experiments, taxodione and arenarone broadened the native-to-unfolded thermal transition (T m ), quite different to the large increases in ΔT m seen with biphosphonate inhibitors. The results identify new classes of FPPS inhibitors, diterpenoids and sesquiterpenoids, that bind to the IPP site and may be of interest as anticancer and antiinfective drug leads.prenyl synthase | crystallography | prenylation | molecular dynamics | drug discovery F arnesyl diphosphate synthase (FPPS) catalyzes the condensation of isopentenyl diphosphate (IPP; compound 1 in Fig. 1) with dimethylallyl diphosphate (DMAPP; compound 2 in Fig. 1) to form the C 10 isoprenoid geranyl diphosphate (GPP; compound 3 in Fig. 1), which then condenses with a second IPP to form the C 15 isoprenoid, farnesyl diphosphate (FPP; compound 4 in Fig. 1). FPP then is used in a wide range of reactions including the formation of geranylgeranyl diphosphate (GGPP) (1), squalene (involved in cholesterol and ergosterol biosynthesis), dehydrosqualene (used in formation of the Staphylococcus aureus virulence factor staphyloxanthin) (2), undecaprenyl diphosphate (used in bacterial cell wall biosynthesis), and quinone and in heme a/o biosynthesis. FPP and GGPP also are used in protein (e.g., Ras, Rho, Rac) prenylation, and FPPS is an important target for the bisphosphonate class of drugs (used to treat bone resorption diseases) such as zoledronate (compound 5 in Fig. 1) (3). Bisphosphonates targeting FPPS have activity as antiparasitics (4), act as immunomodulators (activating γδ T cells containing the Vγ2Vδ2 T-cell receptor) (5), and switch macrophages from an M2 (tumorpromoting) to an M1 (tumor-killing) phenotype (6). They also kill tumor cells (7) and...

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“…68 starting from abietic acid (1) to carry out their biological evaluation (Scheme 56). 71 Firstly, abietic acid (1) was methylated by treatment with LiOH and Me 2 SO 4 to yield ester 377. Regioselective dihydroxylation of 377 with catalytic OsO 4 and Me 3 NO as co-oxidant gave diol 378.…”

Section: Other Approachesmentioning

confidence: 99%

Aromatic abietane diterpenoids: total syntheses and synthetic studies

González

2015

Tetrahedron

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Cytotoxic, immunomodulatory, antimycotic, and antiviral activities of semisynthetic 14-hydroxyabietane derivatives and triptoquinone C-4 epimers

Cited by 26 publications

References 36 publications

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site

Aromatic abietane diterpenoids: total syntheses and synthetic studies

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