Ring A/B-Modified 17β-Hydroxywithanolide Analogues as Antiproliferative Agents for Prostate Cancer and Potentiators of Immunotherapy for Renal Carcinoma and Melanoma.

Abstract

Physachenolide C (1) is a 17β-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 μM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17β-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.

• Authors: E M Kithsiri Wijeratne, Ya-Ming Xu, Manping X Liu, Marielle C Inacio, Alan D Brooks, Poonam Tewary, Thomas J Sayers, A A Leslie Gunatilaka
• Journal: Journal of natural products (J Nat Prod) Vol. 84 Issue 12 Pg. 3029-3038 (12 24 2021) ISSN: 1520-6025 [Electronic] United States
• PMID: 34851111 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Withanolides

Topics

• Antineoplastic Agents (therapeutic use)
• Cell Proliferation (drug effects)
• Humans
• Immunotherapy
• Kidney Neoplasms (therapy)
• Male
• Melanoma (therapy)
• Prostatic Neoplasms (drug therapy, pathology)
• Withanolides (chemistry, therapeutic use)