Affiliation:
1. Department of chemistry of natural compounds V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry NAS of Ukraine Academician Kukhar st. 1 02094 Kyiv Ukraine
2. Department of chemistry of bioactive nitrogen-containing heterocyclic bases V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry NAS of Ukraine Academician Kukhar st. 1 02094 Kyiv Ukraine
Abstract
AbstractSeven TPP+ new 5‐sulfanyl substituted (thiazol‐4‐yl) phosphonium salts functionalized with different substituents were designed, synthesized, and studied against the NCI‐60 human cancer cell lines. Compounds 1–4 show the total average parameters GI50=0.7–2.7 μM, TGI=7.0–14.6 μM, and LC50=25.2–41.8 μM, and compounds 5–7 show GI50=0.3–0.5 μM, TGI=1.3–3.1 μM, and LC50=3.6–4.0 μM. The most active compound 7 demonstrated the best anticancer results against leukemia (K‐562, GI50=0.141 μM; RPMI‐8226, GI50=0.143 μM), ovarian cancer (NCI/ADR‐RES, GI50=0.142 μM), breast cancer (HS578T, GI50=0.175 μM; MDA‐MB‐468, GI50=0.101 μM), melanoma (SK‐MEL‐5, GI50=0.155 μM), and colon cancer (COLO 205, GI50=0.163 μM). All compounds showed low cytotoxicity against the leukemia subpanel (LC50>100 μM). The SAR analysis reveals the critical role of the substitutes at the thiazole C2 and C5 positions. Adding the phenyl, p‐tolyl, or 4‐chlorophenyl group to the C2 position in compounds 5–7 increases anticancer effectiveness. According to the NCI COMPARE analysis, compounds 2–3 showed a very high (r=0.92, 0.81) correlation with morpholino‐doxorubicin. Molecular docking‐analyzing the antitumor mechanism of compounds 1–4 action demonstrated that the DNA chain is a probable biotarget. The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents.