Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers

Llanos, Gabriel G.; Araujo, Liliana; Jiménez, Ignacio A.; Moujir, Laila; Rodrı́guez, Jaime A.; Jiménez, Carlos; Bazzocchi, Isabel L.

doi:10.1016/j.ejmech.2017.09.004

Cited by 29 publications

(36 citation statements)

References 39 publications

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“…Structure-Activity Relationship Analysis. The previous reported SAR studies agree that an α,-unsaturated ketone on ring A, a 5,6-epoxide in ring B and an α,-unsaturated δlactone on side-chain in the WA-framework20 are antitumor structural feature requirements, and more recently, acylation is reported to enhance cytotoxicity 19. In this work, chemical modulation by incorporation of silicon on the WA-framework was investigated.…”

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confidence: 58%

Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells

et al. 2019

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confidence: 58%

Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells

et al. 2019

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“…The structure of the twenty-five known compounds were identified by comparison with their observed and reported NMR data as follows: 4β,27-dihydroxy-1-oxo-witha-2,5,16,24-tetraenolide (5) [20], 4β-hydroxy-1-oxo-witha-2,5,16,24-tetraenolide (6) [20], 4β,27-dihydroxy-1-oxo-witha-2,5,24trien olide (7) [36], 6α-chloro-5β-hydroxywithaferin A ( 27) [27], 4β-formyl-6β,27-dihydroxy-1-oxo-witha-2,24dienolide ( 28) [21], and 4β-formyl-6β,27-dihydroxy-1-oxo-witha-24-enolide ( 29) [21]. These endoperoxides were isolated from the acetone extract of W. aristata; however, these metabolites were not detected in previous works on the dichloromethane extract from this plant [20][21][22]. This may be due not only to their solubility, but also to their stability in the selected solvent.…”

Section: Chemistrymentioning

confidence: 88%

“…Pauq. (Solanaceae), an endemic medicinal plant from the Canary Islands [19], and designed a library of withaferin A-analogues as potent inducers in cancer cells [20][21][22][23]. Therefore, encouraged by previous works [14][15][16][17][18], the current study reports the isolation, structure elucidation and anti-leukemic evaluation of four new (1)(2)(3)(4) and twenty-five known withanolides isolated from the acetone extract of W. aristata.…”

Section: Introductionmentioning

confidence: 99%

Withanolide-Type Steroids from Withania aristata as Potential Anti-Leukemic Agents

et al. 2020

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Leukemia is a blood or bone marrow cancer with increasing incidence in developed regions of the world. Currently, there is an ongoing need for novel and safe anti-leukemic agents, as no fully effective chemotherapy is available to treat this life-threatening disease. Herein, are reported the isolation, structural elucidation, and anti-leukemic evaluation of twenty-nine withanolide-type steroids (1–29) from Withania aristata. Among them, the new isolated withanolides, withaperoxidins A–D (1–4) have an unusual six-membered cyclic peroxide moiety on the withasteroid skeleton as a structural novelty. Their structures have been elucidated by means of spectroscopic analyses, including 2D NMR experiments. In addition, extensive structure–activity relationships and in silico ADME studies were employed to understand the pharmacophore and pharmacokinetic properties of this series of withasteroids. Compounds 15, 16, and 22 together with withaferin A (14) were identified as having improved antiproliferative effect (IC50 ranging from 0.2 to 0.7 μM) on human leukemia HL-60 cell lines compared with the reference drug, etoposide. This cytotoxic potency was also coupled with good selectivity index (SI 33.0–9.2) on non-tumoral Vero cell line and in silico drug likeness. These findings revealed that these natural withasteroids are potential candidates as chemotherapeutic agents in the treatment of leukemia.

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“…In particular, withaferin A, a well-known anticancer drug candidate, exerts its anticancer effect via induction of apoptosis in several human cancer cells [21]. Recent studies have revealed that withaferin A-analogues are potent apoptotic inducers in different tumor cell lines, evidenced by DNA fragmentation, chromatin condensation and phosphatidylserine exposure, indicating an apoptosis mechanism of action in cancer cells [22,23]. Moreover, the leishmanicidal activity of withaferin A has been reported against L. donovani, inducing an apoptosis-like cell death mechanism by inhibiting protein-kinase C, leading to the depolarization of mitochondrial membrane potential and releasing of cytochrome c into the cytosol, which induces formation of ROS inside cells, causing oxidative DNA lesions [24].…”

Section: Withanolides Induce Oxidative Stress In L Amazonensismentioning

confidence: 99%

Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death

et al. 2019

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Leishmaniasis and American trypanosomiasis are parasitic diseases that cause significant clinical, social and economic impact on the population of tropical and subtropical countries. Their current treatment is limited and presents multiple drawbacks, including high toxicity, high cost, lengthy treatment plans, as well as the emergence of resistant species. Therefore, there is a need to find new lead compounds with high potency against parasites and low toxicity in patients. In the present work, the bioguided fractionation of an endemic plant from the Canary Islands, Withania aristata, led to the identification of withanolide-type metabolites (1–3) with leishmanicidal and trypanocidal activities. Compounds 1 and 3 showed a significant dose-dependent inhibition effect on the proliferation of L. amazonensis promastigotes and T. cruzi epimastigotes, higher than the reference drugs, miltefosine and benznidazole, respectively. Moreover, compounds 1–3 were more potent (IC50 0.055–0.663 µM) than the reference drug against the intracellular amastigote stage of L. amazonensis, with a high selectivity index on murine macrophage cells (SI 58.66–216.73). Studies on the mechanism of death showed that the compounds induced programmed cell death or that which was apoptosis-like. The present findings underline the potential of withanolides as novel therapeutic antikinetoplastid agents.

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Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers

Cited by 29 publications

References 39 publications

Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells

Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells

Withanolide-Type Steroids from Withania aristata as Potential Anti-Leukemic Agents

Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death

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