Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues

Abstract

The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was recently reported to possess cytotoxic activity against head and neck squamous cell carcinomas. Semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure-activity relationships, 20 new semisynthetic analogues of withalongolide A were synthesized and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A.

Antiproliferative withanolides from several solanaceous species

“…In order to better probe the withanolide antiproliferative structural activity relationship model, a total of 27 semi-synthetic withanolide derivatives ( 69 – 95 ) were prepared from natural isolates ( 1 , 19 , 20 , and 33 ) (Figure 5) (Zhang et al 2011; Zhang et al 2012b; Motiwala et al 2013). …”

“…Greater potency was observed in the acetylated derivatives withalongolide A 4,19,27-triacetate ( 79 ), withalongolide B 4,19-diacetate ( 73 ), and withalongolide O 4,7-diacetate ( 71 ), which collectively produced IC 50 values in the 0.067 n M – 2.0 μM range (Zhang et al 2011; Zhang et al 2012b; Motiwala et al 2013). …”

The therapeutic potential of Physalis longifolia against various carcinomas

“…Cronquist [4], Physalis longifolia Nutt. [5][6][7], and Withania somnifera Dunal [8,9]. Such extensive research afforded a withanolide library that was utilized as part of an extensive structural activity relationship study.…”

“…Subsequent semi-synthetic experiments were conducted on the most anti-proliferative constituents of the species, such as compound 2, which generated a highly potent withanolide derivative (24) (Fig. 1) [7]. Additional cell proliferation assay testing revealed that withanolides 1, 2, and 24 produced nanomolar IC 50 values (1: 290, 4000, 2000, 800, 200 nM; 2: >10,000, 5100, 5300, 3300 nM, >10,000 nM; and 24: 98 nM; 810 nM; 140 nM; 2200 nM; 410 nM) against melanoma (B16F10 and SKMEL-28), human oral cavity carcinoma (JMAR, and MDA-1986) and normal fetal fibroblast (MRC-5) cells, respectively [5].…”

Chemistry and pharmacology of withania somnifera: An update

“…Aubé and coworkers reported a series of semisynthetic analogs of withalongolide-A, which is a C-19 hydroxylated analog of withaferin-A (Motiwala et al, 2013). These semisynthetic derivatives are found to be more cytotoxic than the parent molecule against a variety of cell lines (Fig.…”