Biologically active natural products from Synadenium grantii and Withania obtusifolia

Phytochemicals were purified and identified from the medicinal plants Withania obtusifolia and Synadenium grantii. Based on spectroscopic data including 1- and 2-D NMR, MS, and UV-VIS analysis, two new withanolides, withafolia A and withafolia B, and seven known withanolides (withanolide J, withanolide K, withanolide S 5-methyl ether, ∆16-withanolide, withanolide T, physaperuvin G, and phyperunolide D) were isolated from the aerial portion of W. obtusifolia. Withanolide J and physaperuvin G, assayed using a 60 tumor-cell-line panel performed by National Cancer Institute (NCI), showed moderate inhibition against lymphoblastic (SR) and promyelocytic (HL-60) leukemia cell lines with growth inhibition of 43 and 38%, respectively. Cytotoxic efficacy of these withanolides were independently assayed in house against the HL-60 cell line. Withanolide J and physapeuvin G exhibited similar anti-tumor activity with IC50 values of 26 and 28 µM, respectively. STAT3, an oncogenic transcription factor that plays a regulatory role in tumor progression and metastasis was targeted for in silico Withanolide-inhibitor studies. Docking studies probed the molecular fit of anti-tumor withanolides in the STAT3 binding site with different protein conformations. In comparison with a commercial STAT3 inhibitor, S3I-201 similar docking scores were observed for withanolide J and physapeuvin G. From the leaves of S. grantii, two previously identified compounds beta-sitosterol and ingol 7,8,12-triacetate 3-phenylacetate were isolated and assayed for anti-tumor activity also using a NCI tumor-cell-line panel. Ingol 7,8,12-triacetate 3-phenylacetate was cytotoxic against leukemia cancer cells (SR) and renal cancer cells (CAKI-1) with growth inhibition of 33 and 21%, respectively. In silico docking study showed robust binding affinity of ingol 7,8,12-triacetate 3-phenylacetate within the active site of PI3Kα, a kinase that regulates PI3K/Akt signaling pathway and involved in cell cycle progression. Mutations of PI3Kα are associated with several human cancers and as such is considered an oncogene. These data suggest a role of ingol 7,8,12-triacetate 3-phenylacetate in tumor inhibition via the PI3K/Akt signaling pathway.

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