Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Riga Stradiņš University, Dzirciema 16, Riga LV-1007, Latvia.
Oxid Med Cell Longev. 2020 Dec 31;2020:8413713. doi: 10.1155/2020/8413713. eCollection 2020.
Three groups of synthetic lipids are chosen for studies: (1) 1,4-dihydropyridines (1,4-DHPs) containing two cationic moieties and their analogues; (2) 3,4-dihydro-2(1)-pyridones containing a cationic moiety; and (3) acyclic, open-chain analogues, i.e., 2-amino-3-alkoxycarbonylalkylammonium derivatives. 1,4-DHPs possessing dodecyl alkyl chains in the ester groups in positions 3 and 5 and cationic nitrogen-containing groups in positions 2 and 6 have high cytotoxicity in cancer cells HT-1080 (human lung fibrosarcoma) and MH-22A (mouse hepatoma), but low cytotoxicity in the noncancerous NIH3T3 cells (mouse embryonic fibroblast). On the contrary, similar compounds having short (methyl, ethyl, or propoxyethyl) chains in the ester groups in positions 3 and 5 lack cytotoxicity in the cancer cells HT-1080 and MH-22A even at high doses. Inclusion of fluorine atoms in the alkyl chains in positions 3 and 5 of the DHP cycle decreases the cytotoxicity of the mentioned compounds. Structurally related dihydropyridones with a polar head group are substantially more toxic to normal and cancerous cells than the DHP analogues. Open-chain analogues of DHP lipids comprise the same conjugated aminovinylcarbonyl moiety and possess anticancer activity, but they also have high basal cytotoxicity. Electrochemical oxidation data demonstrate that oxidation potentials of selected compounds are in the range of 1.6-1.7 V for cationic 1,4-DHP, 2.0-2.4 V for cationic 3,4-dihydropyridones, and 1.2-1.5 V for 2-amino-3-alkoxycarbonylalkylammonium derivatives. Furthermore, the tested cationic 1,4-DHP amphiphiles possess antiradical activity. Molecular topological polar surface area values for the tested compounds were defined in accordance with the main fragments of compound structures. The determined log values were highest for dodecyl ester groups in positions 3 and 5 of the 1,4-DHP and lowest for short alkyl chain-containing amphiphiles.
（1）含有两个阳离子部分的 1,4-二氢吡啶（1,4-DHPs）及其类似物；（2）含有阳离子部分的 3,4-二氢-2(1)-吡啶酮；和（3）无环、开链类似物，即 2-氨基-3-烷氧基羰基烷基铵衍生物。在位置 3 和 5 的酯基中具有十二烷基链和在位置 2 和 6 中具有含阳离子氮的基团的 1,4-DHPs 在癌细胞 HT-1080（人肺纤维肉瘤）和 MH-22A（小鼠肝癌）中具有高细胞毒性，但在非癌细胞 NIH3T3 中（小鼠胚胎成纤维细胞）具有低细胞毒性。相反，在位置 3 和 5 的酯基中具有短（甲基、乙基或乙氧基乙基）链的类似化合物在癌细胞 HT-1080 和 MH-22A 中即使在高剂量下也没有细胞毒性。在 DHP 环的烷基链中引入氟原子会降低所述化合物的细胞毒性。具有极性头基团的结构相关的二氢吡啶酮对正常细胞和癌细胞的毒性要大得多。DHP 脂质的开链类似物包含相同的共轭氨基乙烯基羰基部分，并具有抗癌活性，但它们也具有高的基础细胞毒性。电化学氧化数据表明，所选化合物的氧化电位范围为阳离子 1,4-DHP 为 1.6-1.7 V，阳离子 3,4-二氢吡啶酮为 2.0-2.4 V，2-氨基-3-烷氧基羰基烷基铵衍生物为 1.2-1.5 V。此外，测试的阳离子 1,4-DHP 两亲物具有抗自由基活性。根据化合物结构的主要片段，定义了测试化合物的分子拓扑极性表面积值。对于测试的化合物，确定的 log 值对于 1,4-DHP 中的位置 3 和 5 的十二烷基酯基团最高，对于含有短烷基链的两亲物最低。
