Bruna-Haupt Ezequiel F, Perretti Marcelle D, Garro Hugo A, Carrillo Romen, Machín Félix, Lorenzo-Castrillejo Isabel, Gutiérrez Lucas, Vega-Hissi Esteban G, Mamberto Macarena, Menacho-Marquez Mauricio, Fernández Claudio O, García Celina, Pungitore Carlos R
Department of Chemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, San Luis 5700, Argentina.
Chemical Technology Research Institute-National Council for Scientific and Technical Research (INTEQUI-CONICET), San Luis 5700, Argentina.
ACS Omega. 2023 Jul 13;8(29):26479-26496. doi: 10.1021/acsomega.3c03181. eCollection 2023 Jul 25.
A library of structurally related coumarins was generated through synthesis reactions and chemical modification reactions to obtain derivatives with antiproliferative activity both and . Out of a total of 35 structurally related coumarin derivatives, seven of them showed inhibitory activity in tests against DNA polymerase with IC values lower than 250 μM. The derivatives 4-(chloromethyl)-5,7-dihydroxy--chromen-2-one () and 4-((acetylthio)methyl)-2-oxo--chromen-7-yl acetate () showed the most promising anti-polymerase activity with IC values of 20.7 ± 2.10 and 48.25 ± 1.20 μM, respectively. Assays with tumor cell lines (HEK 293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy--chromen-2-one () was the most promising, with an IC value of 8.47 μM and a selectivity index of 1.87. In addition, the derivatives were evaluated against strains that report about common modes of actions, including DNA damage, that are expected for agents that cause replicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)--chromen-2-one () and 7-(3-(oxiran-2-yl)propoxy)--chromen-2-one () caused DNA damage in . The -alkenylepoxy group stands out as that with the most important functionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the antiretroviral capacity was tested through RT-PCR assays. Derivative showed inhibitory activity below 150 μM with an IC value of 134.22 ± 2.37 μM, highlighting the -butylepoxy group as the functionalization responsible for the activity.
通过合成反应和化学修饰反应生成了一个结构相关香豆素库，以获得具有抗增殖活性的衍生物。在总共35种结构相关的香豆素衍生物中，其中七种在针对DNA聚合酶的测试中显示出抑制活性，IC值低于250μM。衍生物4-(氯甲基)-5,7-二羟基-2H-色原酮( )和4-((乙酰硫基)甲基)-2-氧代-2H-色原酮-7-基乙酸酯( )显示出最有前景的抗聚合酶活性，IC值分别为20.7±2.10和48.25±1.20μM。对肿瘤细胞系(HEK 293和HCT-116)进行了测定，衍生物4-(氯甲基)-7,8-二羟基-2H-色原酮( )最有前景，IC值为8.47μM，选择性指数为1.87。此外，对这些衍生物针对报告常见作用模式（包括DNA损伤）的菌株进行了评估，这些作用模式是引起复制应激的药物所预期的。香豆素衍生物7-(2-(环氧乙烷-2-基)乙氧基)-2H-色原酮( )和7-(3-(环氧乙烷-2-基)丙氧基)-2H-色原酮( )在 中引起DNA损伤。在这35种衍生物家族中，α-烯基环氧基团作为具有最重要功能的基团脱颖而出，作为抗增殖支架呈现出非常好的特性。最后，通过RT-PCR测定法测试了抗逆转录病毒能力。衍生物 显示出低于150μM的抑制活性，IC值为134.22±2.37μM，突出了α-丁基环氧基团作为负责该活性的官能团。
