Cytotoxic 1,2,3-Triazoles as Potential Leads Targeting the S100A2-p53 Complex: Synthesis and Cytotoxicity
- ChemMedChem. 2021 Sep 16;16(18):2864-2881. doi: 10.1002/cmdc.202000950.
- 1. Chemistry, School of Environmental & Life Sciences The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
- 2. Medicinal Chemistry, School of Pharmacy, Binzhou Medical University, Yantai, 264003, China.
- 3. School of Environmental & Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, Australia.
- 4. Nha Trang University No. 2 Nguyen Dinh Chieu Street, Nha Trang City, Khanh Hoa, 8458, Vietnam.
- 5. Experimental Therapeutics Group Department of Medical Oncology, Calvary Mater Newcastle Hospital Edith Street, Waratah, NSW 2298, Australia.
In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic Cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 μM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic Cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 μM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.