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

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...

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Published in:	Journal of natural products (Washington, D.C.) Vol. 80; no. 3; pp. 676 - 683
Main Authors:	Jans, Petra E, Mfuh, Adelphe M, Arman, Hadi D, Shaffer, Corena V, Larionov, Oleg V, Mooberry, Susan L
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society and American Society of Pharmacognosy 24-03-2017
Subjects:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - isolation & purification Antineoplastic Agents - pharmacology Cell Cycle - drug effects Colorectal Neoplasms - drug therapy Dipeptides - chemical synthesis Dipeptides - chemistry Dipeptides - isolation & purification Dipeptides - pharmacology Diterpenes DNA - metabolism Fungi - drug effects HeLa Cells Humans Marine Biology Molecular Structure S Phase - drug effects Structure-Activity Relationship
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Summary:	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.
Bibliography:	Author Contributions: P. E. Jans, A. M. Mfuh, H. D. Arman, C. V. Shaffer contributed equally.
ISSN:	0163-3864 1520-6025
DOI:	10.1021/acs.jnatprod.6b00963