2. Academic Validation
  3. 3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety

3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety

  • Bioorg Med Chem Lett. 2022 Apr 1;61:128591. doi: 10.1016/j.bmcl.2022.128591.
Jufeng Sun 1,  Joey I Ambrus 2,  Jennifer R Baker 2,  Cecilia C Russell 2,  Peter J Cossar 2,  Jennette A Sakoff 3,  Christopher J Scarlett 4,  Adam McCluskey 5
Affiliations

Affiliations

  • 1 Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Medicinal Chemistry, School of Pharmacy, Binzhou Medical University, Yantai 264003, China.
  • 2 Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
  • 3 Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital, Edith Street, Waratah, NSW 2298, Australia.
  • 4 Applied Sciences, School of Environmental & Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, Australia.
  • 5 Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Electronic address: [email protected].
PMID: 35114371 DOI: 10.1016/j.bmcl.2022.128591
Abstract

Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic Cancer. It is a validated pancreatic Cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic Cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total. Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of Cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic Cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 to 30 μM against cohort-1 and 1.4-30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2-3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.

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