Synthesis, characterization, and in vitro anticancer evaluation of 2,4 disulfonylsubstituted 5-aminothiazoles

Current Chemistry Letters 13 (2024) 557–568 Contents lists available at GrowingScience Current Chemistry Letters homepage: www.GrowingScience.com Synthesis, characterization, and in vitro anticancer evaluation of 2,4-disulfonylsubstituted 5aminothiazoles Volodymyr Zyabreva, Bohdan Demydchuka, Stepan Pilyoa, Victor Zhirnova, Olexandr Liavynetsb and Volodymyr Brovaretsa* a Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Akademika Kukharya Str., 1, Kyiv, 02094, Ukraine b Department of General Chemistry and Chemistry of Materials, Yuriy Fedkovych Chernivtsi National University, Kotsyubynsky Str., 2, Chernivtsi, 58012, Ukraine CHRONICLE Article history: Received October 2, 2023 Received in revised form January 5, 2024 Accepted February 8, 2024 Available online February 8, 2024 Keywords: 4-Arylsulfonyl-1,3-thiazoles Design Synthesis Anticancer activity COMPARE correlations ABSTRACT Novel 2,4-disulfonylsubstituted 5-aminothiazoles were synthesized and their anticancer activity was assessed at a high dose (10 μM) against NCI 60 cancer cell lines. Compounds 24 and 25 showed the antiproliferative activity with mean growth inhibition about 66.0%. Replacing 4hydroxypiperidine 24 with the more hydrophilic N-methyl piperazine 25 increased the number of sensitive cell lines while replacing these hydrophilic groups with lipophilic ones abolished the anticancer activity. The COMPARE analysis showed that the tested compounds had a moderate positive correlation with alkylating agents (CCNU and methyl CCNU) and with a purine nucleotide biosynthesis inhibitor analog (L-cysteine). The results indicate that the above mechanisms of antitumor action of standard compounds are not the main ones for the tested compounds due to the lack of a high correlation. The results of this study allow us to consider compounds 24 and 25 as a basis for their further functionalization to obtain more active compounds. © 2024 by the authors; licensee Growing Science, Canada. 1. Introduction Cancer, resulting from the uncontrolled proliferation of undifferentiated cells, is a severe disease worldwide. Among cancer treatment methods, chemotherapy is the primary method in which cancer cells are destroyed using a variety of natural and synthetic compounds. Despite significant progress in the development of new chemotherapeutic agents, cancer treatment remains a complex problem due to the toxicity, resistance, and lack of selectivity of currently available anticancer drugs. Thiazole is a 5-membered heterocycle containing sulfur and nitrogen atoms, which has multiple reaction sites and serves as a backbone in several compounds widely used in drug development. Its derivatives have a broad spectrum of biological activity interacting with various molecular targets, presented in more than 18 drugs approved by the FDA for clinical use.1 Among them are compounds that control cell proliferation and apoptosis and have antitumor activity, such as alpelisib, dasatinib, dabrafenib, ixabepilone, patellamide A and epothilone.2 The synthesis of thiazole derivatives interacting with various molecular targets and structure-function relationships to support rational design in the construction of thiazolebased anticancer agents is the focus of recent literature reviews on developing novel compounds with anticancer potential.35 It was previously shown that sulfonyl-containing derivatives of some azoles demonstrated high antiproliferative and cytotoxic activity against various cancer cell lines,6-9 which served as the basis for the design, synthesis, and evaluation of the anticancer activity of thiazole sulfonyl derivatives presented in this work. * Corresponding author. Tel: +91-9449140275 E-mail address (V. Brovarets) © 2024 by the authors; licensee Growing Science, Canada doi: 10.5267/j.ccl.2024.2.003 558 2. Results and Discussion 2.1 The one dose assay Most of the synthesized compounds did not show anticancer activity against cell lines of the total panel. Compounds 123 inhibited the growth of most cell lines tested by less than 20%. However, compounds 24 and 25 demonstrated antiproliferative activity against some cell lines of most subpanels, except for the CNS and Prostate subpanels for both compounds and Ovarian for 24 (Table 1). These compounds showed cytotoxicity only against the Breast cancer MDAMB-468 cell line. Table 1. One dose anticancer screening data of the most active compounds against NCI-60 human tumor cell lines Cancer cell subpanel Compound Leukemia 24 25 CCRF-CEM (76) HL-60(TB) (65) K-562 (71) MOLT-4 (62) SR (84) CCRF-CEM (80) HL-60(TB) (82) K-562 (84) MOLT-4 (70) SR (84) Lung Colon Melanoma NCI-H460 (54) NCI-H522 (80) HCT-15 (77) SW-620 (55)- LOX IMVI (50) MDA-MB-435 (83) UACC-62 (58) NCI-H460 (60) NCI-H522 (85) HCT-116 (53) HCT-15 (75) SW-620 (64)- LOX IMVI (70) MDA-MB-435 (92) SK-MEL-2 (51) UACC-62 (52) Ovarian OVCAR-3 (54) OVCAR-8 (52) NCI/ADR-RES (56) Renal Breast RXF 393 (66) MCF7 (57) BT-549 (51) MDA-MB-468 (121) 786-0 (53) RXF 393 (70) SN12C (54) MCF7 (57) BT-549 (57) T-47D (62) MDA-MB-468 (115) The compounds were added at a concentration (1∙10-5 M), and the culture was incubated for 48 h. The number reported for the one-dose assay is growth inhibition (%) relative to the no-drug control and relative to the time-zero number of cells. This allows the detection of growth inhibition (values between 0 and 100) and lethality (values more than 100). A value of 200 means all cells are dead. The percentage of growth inhibition of compounds is shown in parentheses. Compounds 24 and 25 showed the same non-selective antiproliferative activity against cell lines of the NCI 60 total panel with mean growth inhibition values of 65.9±3.1 and 66.0±2.8%, respectively. However, compound 25, unlike 24, inhibited the growth of 3 cell lines of Ovarian cancer and exceeded the latter in terms of the number of sensitive lines (24 and 16, respectively). The number of cell lines of each subpanel sensitive to compound 25, expressed as a percentage, is as follows: (the number of lines is given in brackets): Leukaemia - 83 (5), breast - 67 (4), Ovarian - 57 (4), Melanoma - 50 (4), Colon - 50 (3), Renal - 43 (3) and Lung - 29 (2) and to compound 24: Leukaemia - 83 (5), breast - 50 (3), Melanoma - 38 (3), Colon - 33 (2), Lung - 29 (2) and Renal- 14 (1). The structures of these compounds differed only in the substituents in the fifth position of the oxazole; that is, according to PubChem (https://pubchem.ncbi.nlm.nih.gov/), the replacement of 4-hydroxypiperidine (XLogP3-AA = -0.3) with the more hydrophilic N-methyl piperazine (XLogP3-AA = -0.4) led to an increase in the number of sensitive cell lines, whereas replacement of these hydrophilic groups with lipophilic isopropyl amine (XLogP3-AA = 0.1), furan-2-ylmethylamine, diethylamine (XLogP3 = 0.6), or pipepredine (XLogP3 = 0.8), giving compounds 20- (...truncated)