Cyclopentenone-Containing Tetrahydroquinoline and Geldanamycin Alkaloids from Streptomyces malaysiensis as Potential Anti-Androgens against Prostate Cancer Cells

Abstract

Malaymycin (1), a new cyclopentenone-containing tetrahydroquinoline alkaloid, and mccrearamycin E (2), a geldanamycin analogue bearing a rare ring-contracted cyclopentenone moiety, and a C 2-symmetric macrodiolide (7) were isolated from Streptomyces malaysiensis SCSIO41397. Their structures including absolute configurations were determined by detailed analyses of NMR and HRMS data and ECD calculations. The occurrence of mccrearamycin E (2) bearing a ring-contracted cyclopentenone is rare in the geldanamycin class. All isolated compounds were evaluated for their cytotoxicities against five cancer cell lines. As a result, compounds 1, 4, 5, and 7 showed cytotoxicity against some or all of the five cancer cell lines with IC50 values ranging from 0.067 to 7.2 μM. In particular, compound 1 inhibited the growth of C42B and H446 cell lines with IC50 values of 67 and 70 nM, respectively. Malaymycin (1) significantly induced cell cycle arrest at the G0/G1 phase in C42B cell lines and caused cell shrinkage and inhibited the expression of the androgen receptor (AR) at both the mRNA and protein levels in a dose-dependent manner. Further examination by qRT-PCR analysis showed that 1 strongly suppressed the expression of AR target genes KLK2 and KLK3 in the C42B and 22RV1 cell lines, which suggested that 1 might be a promising potential lead compound for the development of a treatment for the castration-resistant prostate cancer (CRPC).

Global regulatory factor FsveA up-regulate the production of antitumor substance in endophytic Fusarium solani

“…In the differential substances we screened, the fraction of alkaloid compounds (including Geldanamycin, AICAR and Nucleosides) is likewise higher. Among them, Geldanamycin is reported to be a natural HSP90 inhibitor with good inhibitory activity against the growth of various tumor cells and has broad-spectrum anti-proliferative and anti-tumor effects (Xie et al 2021). AICAR can induce apoptosis and inhibit migration and invasion of prostate cancer cells through the Ampk/Mtor-dependent pathway (Su et al 2019).…”

Marine natural products

“…Malaymycin also suppresses the expression of AR target genes KLK2 and KLK3 in the C42B cell line, making it a promising lead compound for castration-resistant prostate cancer. 58 …”

“…Furthermore, MOA studies showed that 184 induced cell cycle arrest in the G0/G1 phase in a C42B (prostate cancer) cell line, caused cell shrinkage and inhibited the expression of the androgen receptor (AR). Malaymycin also suppresses the expression of AR target genes KLK2 and KLK3 in the C42B cell line, making it a promising lead compound for castration-resistant prostate cancer 58. Through efforts to discover lead compounds against the rare cancer pseudomyxoma peritonei (PMP) ve new angucyclines, grincamycins P-T 187-191, from a Streptomyces sp.…”

New Diterpene and Indole Alkaloid Analogs from the Streptomyces malaysiensis SCSIO 41397

“…[9] In our previous study, a new cyclopentenone-containing tetrahydroquinoline alkaloid (malaymycin), and a geldanamycin analog bearing a rare ring-contracted cyclopentenone moiety (mccrear-amycin E) were isolated from Streptomyces malaysiensis SCSIO 41397. [10] Due to the abundant secondary metabolites of this strain, we isolated its fermentation products again in order to find more unknown secondary metabolites. This time a total of 11 compounds were isolated, including a new cyclooctatintype [11] diterpene, 15-hydroxycyclooctatin (1), and a new streptoprenylindole-type [12] indole alkaloid, streptoprenylindole D (3).…”

“…These NPs often possess diverse biological activities, such as antitumor, [5] antibacterial, [6] antiviral, [7] antiparasitic, [8] etc., so they have significant implications for drug development [9] . In our previous study, a new cyclopentenone‐containing tetrahydroquinoline alkaloid (malaymycin), and a geldanamycin analog bearing a rare ring‐contracted cyclopentenone moiety (mccrearamycin E) were isolated from Streptomyces malaysiensis SCSIO 41397 [10] . Due to the abundant secondary metabolites of this strain, we isolated its fermentation products again in order to find more unknown secondary metabolites.…”