title: 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 IC50values 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 IC85concentration, 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.
authors.forename: Petra E
authors.initials: PE
authors.lastname: Jans
authors.affiliation: Department of Chemistry, The University of Texas at San Antonio , San Antonio, Texas 78249-0698, United States.
authors.forename: Adelphe M
authors.initials: AM
authors.lastname: Mfuh
authors.affiliation: Department of Chemistry, The University of Texas at San Antonio , San Antonio, Texas 78249-0698, United States.
authors.forename: Hadi D
authors.initials: HD
authors.lastname: Arman
authors.forename: Corena V
authors.identifier: 0000-0002-6183-1110
authors.initials: CV
authors.lastname: Shaffer
authors.affiliation: Department of Chemistry, The University of Texas at San Antonio , San Antonio, Texas 78249-0698, United States.
authors.forename: Oleg V
authors.identifier: 0000-0002-3026-1135
authors.initials: OV
authors.lastname: Larionov
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004247:DNA / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004224:Diterpenes; D005658:Fungi / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008386:Marine Biology; D015394:Molecular Structure; D016196:S Phase / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D004224:Diterpenes; C476748:trichodermamide B; C529906:trichodermamide C; D004247:DNA