Tiwari Laxmi, Leach Caleb, Williams Ashley, Lighter Brandon, Heiden Zachariah, Roll Mark F, Moberly James G, Cornell Kenneth A, Waynant Kristopher V
Department of Chemistry, University of Idaho, Moscow, Idaho 83844, United States.
Department of Chemistry and Biochemistry, Boise State University, Boise, Idaho 83725, United States.
ACS Omega. 2024 Aug 20;9(35):37141-37154. doi: 10.1021/acsomega.4c04216. eCollection 2024 Sep 3.
Finding new sources of biologically active compounds for anticancer or antimicrobial therapies remains an active area of research. Azothioformamides (ATFs) with a 1,3 N=N-C=S heterodiene backbone are a new class of biologically active compounds that chelate metals (e.g., Cu) forming stable ATF metal coordination complexes. In this study, ATF ligands were prepared with pyrrolidine, piperidine, -methylpiperazine, and morpholine substituents on the formamide as to add more heterocyclic drug-like character for biological studies. Formamide derivatives were then complexed with various Cu(I) salts to form coordination complexes. Cu(I) salts were selected as to create potential bioactive compounds with less toxicity. Binding association constants of each Cu(I) salt to ATF ligands were extrapolated from UV-vis titration studies and were corroborated with DFT calculations using a hybrid functional B3LYP method. It was observed that the smaller pyrrolidine functionalized ATFs bound to the Cu(I) salts had stronger binding than any of the larger six-membered-ring heterocycles with association values in the 10 - 10 M range. The ATF-Cu(I) salt coordination complexes were then evaluated for antimicrobial activity against two bacteria (, ), one yeast (), four human cancer lines (A-549, K-562, HT-1080, MDA-MB-231), and two normal human lines (MRC-5, HFF). The ATF ligands themselves were inactive against all microbes and most human lines except K-562 cells, which were sensitive to three of the four ligands (IC's = 7.0-25.5 μM). Most ATF-Cu(I) complexes showed low to medium micromolar activity against (IC's 2.6-24.8 μM) and (IC's = 3.4-37.7 μM), with increasing activity corresponding to complexes with higher binding association constants. The antiproliferative properties of ATF-Cu(I) metal salt complexes against mammalian cells were mixed, with low to medium micromolar activity across all cell lines. Notably, several ATF-Cu(I) salt coordination complexes showed submicromolar activity against the HT-1080 fibrosarcoma line (0.52-0.69 μM). The results demonstrate promising activity of ATF-Cu(I) complexes, particularly with pyrrolidine as the formamide component. These studies suggest that the stronger binding association values correlate to higher levels of biological activity.
寻找用于抗癌或抗菌治疗的生物活性化合物新来源仍是一个活跃的研究领域。具有1,3 N=N-C=S杂二烯主链的氮硫甲酰胺（ATF）是一类新型生物活性化合物，可螯合金属（如铜）形成稳定的ATF金属配位络合物。在本研究中，制备了在甲酰胺上带有吡咯烷、哌啶、N-甲基哌嗪和吗啉取代基的ATF配体，以便为生物学研究增添更多类杂环药物特性。然后将甲酰胺衍生物与各种Cu(I)盐络合形成配位络合物。选择Cu(I)盐以制备毒性较小的潜在生物活性化合物。通过紫外可见滴定研究推断每种Cu(I)盐与ATF配体的结合缔合常数，并使用混合泛函B3LYP方法通过密度泛函理论（DFT）计算进行了验证。观察到，与Cu(I)盐结合的较小的吡咯烷官能化ATF的结合比任何较大的六元环杂环更强，缔合值在10⁻⁶ - 10⁻⁹ M范围内。然后评估了ATF-Cu(I)盐配位络合物对两种细菌（大肠杆菌、金黄色葡萄球菌）、一种酵母（白色念珠菌）、四种人类癌细胞系（A-549、K-562、HT-1080、MDA-MB-231）和两种正常人细胞系（MRC-5、HFF）的抗菌活性。ATF配体本身对所有微生物和大多数人类细胞系均无活性，但K-562细胞除外，该细胞系对四种配体中的三种敏感（IC₅₀ = 7.0 - 25.5 μM）。大多数ATF-Cu(I)络合物对大肠杆菌（IC₅₀ 2.6 - 24.8 μM）和金黄色葡萄球菌（IC₅₀ = 3.4 - 37.7 μM）表现出低至中等微摩尔活性，活性增加对应于具有更高结合缔合常数的络合物。ATF-Cu(I)金属盐络合物对哺乳动物细胞的抗增殖特性各异，在所有细胞系中均表现出低至中等微摩尔活性。值得注意的是，几种ATF-Cu(I)盐配位络合物对HT-1080纤维肉瘤细胞系表现出亚微摩尔活性（0.52 - 0.69 μM）。结果表明ATF-Cu(I)络合物具有良好的活性，特别是以吡咯烷作为甲酰胺组分时。这些研究表明，更强的结合缔合值与更高水平的生物活性相关。
