Cytotoxicity and Mechanism of Action of the Marine-Derived Fungal Metabolite Trichodermamide B and Synthetic Analogues

Abstract

The trichodermamides are modified dipeptides isolated from a wide variety of fungi, including Trichoderma virens. Previous studies reported that trichodermamide B (2) initiated cytotoxicity in HCT-116 colorectal cancer cells, while trichodermamide A (1) was devoid of activity. We recently developed an efficient total synthesis for the trichodermamides A–C (1–3). Multiple intermediates and analogues were produced, and they were evaluated for biological effects to identify additional structure activity relationships and the possibility that a simplified analogue would retain the biological effects of 2. The antiproliferative effects of 18 compounds were evaluated and the results show that 2 and four other compounds are active in HeLa cells, with IC50 values in the range of 1.4–21 μM. Mechanism of action studies of 2 and the other active analogues revealed different spectra of activity. At the IC85 concentration, 2 caused S-phase accumulation and cell death in HeLa cells, suggesting response to DNA double strand breaks. The analogues did not cause S-phase accumulation or induction of DNA damage repair pathways, consistent with an alternate mode of action. The mechanistic differences are hypothesized to be due to the chlorohydrin moiety in 2 which is lacking in the analogues, which could form a DNA-reactive epoxide.

A Computational Approach to Explore the Interaction of Semisynthetic Nitrogenous Heterocyclic Compounds with the SARS-CoV-2 Main Protease

“…Library L3 comprises analogues with the truncated pyrrolidine ring, while library L4 contains structural analogues with the pyrrolidine ring bioisosterically replaced by the partially saturated 1,2-oxazine. Furthermore, 1,2-oxazine systems are encountered in several classes of biologically active natural products, most notably in the trichodermamide series [ 28 , 29 ]. These structurally novel derivatives of HPI natural products can be readily accessed by an inverse electron demand hetero-Diels-Alder reaction of indoles and transient nitrosoalkenes [ 30 ].…”

Trichodermamides D–F, heterocyclic dipeptides with a highly functionalized 1,2-oxazadecaline core isolated from the endophytic fungus Penicillium janthinellum HDN13-309

“…In addition, the chemical shi of C-7 (d C 67.0) also indicated that the hydroxyl group was located at C-7. Thus the planar structure of compound 1 was established and the D 5,6 and 7-OH distinguished 1 from other known trichodermamides such as compounds 4-6 (D 6,7 and 5-OH). The relative conguration of 1 was deduced as 4S*, 7R*, 8R*, 9S* on the basis of the NOESY data and coupling constants.…”

“…5 Driven by the structural novelty and potent bioactivity, total synthesis of trichodermamides A-C have been achieved. [6][7][8] In our previous research, a serious of cytotoxic gliovirins (penicisulfuranols A-F) have been isolated from an active endophytic fungus Penicillium janthinellum HDN13-309.…”

Marine Fungi: A Source of Potential Anticancer Compounds

“…In the present study trichodermamide B ( 188 ; Figure 6 ) showed an IC 50 value of 3.1 μM in HeLa cell line. Compound (189) caused S-phase accumulation and cell death in HeLa cells, suggesting response to DNA double strand breaks (Jans et al, 2017 ). Chromosulfine ( 189 ; Figure 6 ), a novel cyclopentachromone sulfide, was isolated from a neomycin-resistant mutant of the marine-derived fungus, Penicillium purpurogenum G59.…”