Cytotoxicity and Mechanism of Action of the Marine-Derived Fungal Metabolite Trichodermamide B and Synthetic Analogues.
Cytotoxicity and Mechanism of Action of the Marine-Derived Fungal Metabolite Trichodermamide B and Synthetic Analogues.
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DOI：
10.1021/acs.jnatprod.6b00963
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发表时间：
2017-03-24
影响因子：
5.1
通讯作者：
Mooberry SL
中科院分区：
文献类型：
--
作者：
Jans PE;Mfuh AM;Arman HD;Shaffer CV;Larionov OV;Mooberry SL
木霉酰胺是从多种真菌中分离出来的修饰过的二肽，包括木霉。先前的研究报道木霉酰胺B(2)在HCT-116结直肠癌细胞中启动细胞毒性，而木霉酰胺A(1)缺乏活性。我们最近开发了一种高效的木霉酰胺A-C（1-3）的全合成方法。我们生产了多种中间体和类似物，并对它们的生物效应进行了评估，以确定额外的结构活性关系，以及简化类似物保留2的生物效应的可能性。结果表明，2和4种化合物对HeLa细胞有抑制作用，IC50值在1.4 ~ 21 μM范围内。2和其他活性类似物的作用机理研究显示出不同的活性谱。在IC85浓度下，2在HeLa细胞中引起s期积累和细胞死亡，提示对DNA双链断裂的反应。类似物不会引起s期积累或诱导DNA损伤修复途径，与另一种作用模式一致。机制上的差异被假设是由于2中的氯丙烷部分在类似物中缺乏，这可以形成dna反应性环氧化物。
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.
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影响因子：
5.2
作者：
Seephonkai, Prapairat;Kongsaeree, Palangpon;Thebtaranonth, Yodhathai
通讯作者：
Thebtaranonth, Yodhathai
影响因子：
3.8
作者：
BOYD, MR;PAULI, KD
通讯作者：
PAULI, KD
影响因子：
3.4
作者：
Millward, Michael;Mainwaring, Paul;Spear, Matthew A.
通讯作者：
Spear, Matthew A.
影响因子：
3.6
作者：
Sperry, S;Samuels, GJ;Crews, P
通讯作者：
Crews, P
影响因子：
5.4
作者：
Bhatnagar I;Kim SK
通讯作者：
Kim SK