title: Design, Synthesis, and in vitro and in vivo Evaluations of (Z)-3,4,5-Trimethoxystyrylbenzenesulfonamides/sulfonates as Highly Potent Tubulin Polymerization Inhibitors.
abstract: Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug-discovery processes. Structure-based docking studies illustrate the basic underlying concepts and reveal that interactions of the sulfonamide group and hydrophobic interactions are crucial. On the basis of this strategy, over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of 60 human cancer cell lines; the majority of these compounds exhibited promising cytotoxicity with GI50values ranging between 18 and 50 nm. Among these compounds, (Z)-N-[2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (7 a) and (Z)-N-[2-hydroxy-3-methoxy-6-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (9 a) were found to be potent. Similar results were obtained against three human cancer cell lines with IC50values ranging between 0.04 and 3.0 μm. Studies aimed at elucidating the mechanism of action of these new analogues revealed that they inhibited the in vitro polymerization of tubulin and disorganized the assembly of microtubules in HeLa and MCF-7cancer cells. Lead compounds 7 a and 9 a displayed notable in vivo antitumor activity in a HeLa tumor xenograft model. Our studies have resulted in the identification of a scaffold that can target tubulin polymerization, which should have significant potential toward the development of new antitumor drugs.
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Rasala
authors.initials: R
authors.lastname: Mahesh
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Vadithe Lakshma
authors.initials: VL
authors.lastname: Nayak
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Korrapati Suresh
authors.initials: KS
authors.lastname: Babu
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Syed
authors.initials: S
authors.lastname: Riyaz
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Thokhir Basha
authors.initials: TB
authors.lastname: Shaik
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Gajjela Bharth
authors.initials: GB
authors.lastname: Kumar
authors.affiliation: University of Houston, 4800 Calhoun Road, Houston, TX, 77004, USA.
authors.forename: Prema Latha
authors.initials: PL
authors.lastname: Mallipeddi
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Challa Ratna
authors.initials: CR
authors.lastname: Reddy
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.
authors.forename: Kunta Chandra
authors.initials: KC
authors.lastname: Shekar
authors.affiliation: CSIR-CCMB, Uppal Road, Hyderabad, 500007, India.
authors.forename: Jedy
authors.initials: J
authors.lastname: Jose
authors.affiliation: CSIR-CCMB, Uppal Road, Hyderabad, 500007, India.
authors.forename: Narayana
authors.initials: N
authors.lastname: Nagesh
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-IICT, Uppal Road, Hyderabad, 500007, India.|Department of Medicinal Chemistry, NIPER-Hyderabad, 40, Dilip Road, Hyderabad, 500037, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
mesh_terms: D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D058105:Polymerization; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects*
chemical_list: D014404:Tubulin
keywords: antitumor agents; cytotoxicity; immunohistochemistry; molecular modeling; polymerization