Petromurin C

Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show in this study that petromurin C, which was isolated from the culture extract of the marine-derived fungusAspergillus candidusKUFA0062, isolated from the marine spongeEpipolasissp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether, our results provide preliminary indications that petromurin C provides anti-leukemic effects alone or in combination with gilteritinib.

A previously unreportedbis-indolyl benzenoid, candidusin D (2e) and a new hydroxypyrrolidine alkaloid, preussin C (5b) were isolated together with fourteen previously described compounds: palmitic acid, clionasterol, ergosterol 5,8-endoperoxides, chrysophanic acid (1a), emodin (1b), sixbis-indolyl benzenoids including asterriquinol D dimethyl ether (2a), petromurin C (2b), kumbicin B (2c), kumbicin A (2d), 2″-oxoasterriquinol D methyl ether (3), kumbicin D (4), the hydroxypyrrolidine alkaloid preussin (5a), (3S, 6S)-3,6-dibenzylpiperazine-2,5-dione (6) and 4-(acetylamino) benzoic acid (7), from the cultures of the marine sponge-associated fungusAspergillus candidusKUFA 0062. Compounds1a,2a-e,3,4,5a-b, and6were tested for their antibacterial activity against Gram-positive and Gram-negative reference and multidrug-resistant strains isolated from the environment. Only5aexhibited an inhibitory effect againstS. aureusATCC 29213 andE. faecalisATCC29212 as well as both methicillin-resistantS. aureus(MRSA) and vancomycin-resistant enterococci (VRE) strains. Both1aand5aalso reduced significant biofilm formation inE. coliATCC 25922. Moreover,2band5arevealed a synergistic effect with oxacillin against MRSAS. aureus66/1 while5aexhibited a strong synergistic effect with the antibiotic colistin againstE. coli1410/1. Compound1a,2a-e,3,4,5a-b, and6were also tested, together with the crude extract, for cytotoxic effect against eight cancer cell lines: HepG2, HT29, HCT116, A549, A 375, MCF-7, U-251, and T98G. Except for1a,2a,2d,4,and6, all the compounds showed cytotoxicity against all the cancer cell lines tested.