title: Improving both aqueous solubility and anti-cancer activity by assessing progressive lead optimization libraries.
abstract: Thiazolidinone compounds 1-3 are lead compounds that have cytoselective toxicity toward non-small cell lung cancer (NSCLC) cells and drug-resistant NSCLC cells while showing low toxicity to normal human fibroblasts (NHFB). However, this class of compounds generally has a very low aqueous solubility (∼0.1 μg/ml). In order to improve both solubility and anti-cancer activity, we designed and synthesized two lead-optimization libraries and investigated these libraries using simultaneous high-throughput solubility and cytotoxicity assays. By all-around modifications on R(1), R(2) and R(3) substitutions, consecutive library synthesis, and testing, we improved the aqueous solubility (5-fold improvement in solubility, from 0.1 to 0.5 μg/ml) and anti-cancer activity (10-fold improvement in EC50 from 0.72-0.98 μM to 0.08-0.16 μM) in the new lead thiazolidinone compound 31.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Rutgers University, Camden, NJ, United States; The Rutgers Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, United States.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Rutgers University, Camden, NJ, United States; The Rutgers Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. Electronic address: drbingyan@yahoo.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry* / Q000494:pharmacology*; D014867:Water / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D053778:Thiazolidines; D014867:Water
keywords: Aqueous solubility; Cytotoxicity; Lead optimization; NSCLC; Thiazolidinone
references.citation: Drug Discov Today. 2012 May;17(9-10):486-95
references.pmid: 22138563
references.citation: J Pharmacol Sci. 2013;122(3):223-31
references.pmid: 23877018
references.citation: Cancer Res. 2014 Jun 1;74(11):2913-21
references.pmid: 24840647
references.citation: Eur J Med Chem. 2013 May;63:378-86
references.pmid: 23514631
references.citation: J Med Chem. 2006 Jul 27;49(15):4526-34
references.pmid: 16854058
references.citation: J Med Chem. 2010 Oct 14;53(19):6838-50
references.pmid: 20809634
references.citation: Bioorg Med Chem. 2004 Mar 1;12 (5):1091-9
references.pmid: 14980621
references.citation: Biochem Pharmacol. 2013 Aug 1;86(3):351-60
references.pmid: 23743233
references.citation: J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
references.pmid: 11274893
references.citation: J Gen Physiol. 2004 Aug;124(2):125-37
references.pmid: 15277574
references.citation: J Med Chem. 2008 Mar 13;51(5):1242-51
references.pmid: 18257542