title: Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity.
abstract: Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development.
authors.affiliation: Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Maged
authors.initials: M
authors.lastname: Henary
authors.affiliation: Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA; Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Lakshminarayana
authors.initials: L
authors.lastname: Narayana
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ahad
authors.affiliation: Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Sushma R
authors.initials: SR
authors.lastname: Gundala
authors.affiliation: Advinus Therapeutics Limited, Bangalore, Karnataka, India.
authors.forename: Rao
authors.initials: R
authors.lastname: Mukkavilli
authors.affiliation: Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Owens
authors.affiliation: Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA; Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Yadav
authors.affiliation: Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Mulpuri
authors.initials: M
authors.lastname: Nagaraju
authors.affiliation: Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Hamelberg
authors.affiliation: Department of Chemistry, University of Delhi, India; Special Centre of Molecular Medicine, Jawaharlal Nehru University, Delhi, India.
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
authors.forename: Dulal
authors.initials: D
authors.lastname: Panda
authors.affiliation: Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA. Electronic address: raneja@gsu.edu.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006041:Goats; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology; D009665:Noscapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012995:Solubility; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry*
chemical_list: D006131:Growth Inhibitors; D050257:Tubulin Modulators; D014867:Water; D009665:Noscapine
keywords: Antiproliferative; Noscapine; Pharmacokinetics; Tubulin binding; Water solubility