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, 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.

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Microtubules are intrinsic dynamic polymers but programmed regulation of microtubule dynamics through different phases of cell cycle is modulated by numerous proteins known as microtubules associated proteins (MAPs) and mitotic kinases. Proper attachment of microtubules with kinetochore and adequate tension generation leads to chromosomal congression at metaphase plate, that is followed by movement of sister chromatids towards opposite poles of cells. Impairment, in this process activates spindle assembly checkpoint proteins that hamper cell cycle progression and thus maintains genetic stability. Thus, regulation of microtubule dynamics is important in normal cell cycle progression and to prevent aneuploidy.

Most common pattern of Bacterial division is binary fission. Bacterial division occurs by the construction of Z-ring at appropriate time and at a defined site. FtsZ is the major component of Z-ring formation, and the polymerization of FtsZ is regulated in space and time by negative and positive regulators of FtsZ assembly. In the bacterial cell positive and negative regulators help in attaining a critical concentration gradient, such that at mid cell the critical concentration required for Z-ring formation is lowest, thus Z-ring formation takes place at this site only.

Microtubules are tubulin polymers that use nucleoside triphosphate (GTP) hydrolysis for polymerization. Microtubules (MTs) are involved in diverse and dynamic cellular functions like cell shape maintenance, cell division, cell migration, and signalling. Microtubules display dynamic behaviour of Treadmilling and microtubule dynamics, these processes are precisely regulated by microtubule associated proteins. Inside the cells, soluble and polymeric fraction of tubulin is in equilibrium state that is regulated by microtubule polymerizing and depolymerizing proteins.