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Development of 9-(N-arylmethylamino) congeners of noscapine: the microtubule targeting drugs for the management of breast cancer.

ABSTRACT: Noscapine is a natural lead molecule with anticancer activity at a higher concentrations. So, there is an urge for the development of more potent derivatives of noscapine. In this study, we have approached for development of 9-N-arylmethylamino derivatives of noscapine that kills cancer cells without affecting the normal cells. They were designed by substituting N-aryl methyl pharmacophore at the C-9 position and screened out top-ranked three derivatives 13a-c using molecular docking. Further, their theoretical free energy of binding with tubulin was calculated followed by chemical synthesis and experimental validation. In vitro antiproliferative activity of noscapine and its 9-N-arylmethylamino derivatives (13a-c) was carried out using MCF-7 (a triple receptors positive) and MDA-MB-231 (a triple receptor negative) breast cancer cell lines. Further, cytotoxicity to normal cells was examined using human embryonic kidney cells (HEK cells). Inhibition to cell cycle progression and induction of apoptosis was monitored using FACS. The binding of noscapine and 13a-c with tubulin was examined using fluorescence quenching assay. The 9-N-arylmethylamino derivatives of noscapine (13a-c) were found to inhibit the proliferation of cancer cells at a much lower concentration (IC₅₀ values range between 9.1 to 47.3 µM) compared to noscapine (IC₅₀ value is 45.8-59.3 µM). Surprisingly, the proliferation of HEK cells was not inhibited even at a concentration of 100 µM (cytotoxicity is < 5%). These derivatives induced apoptosis by arresting cells at G2/M-phase and also bind to tubulin. The 9-(N-arylmethylamino) noscapinoids have the potential to be a novel therapeutic agent for the treatment of breast cancer.

Supplementary information

The online version contains supplementary material available at 10.1007/s13205-022-03445-3.

SUBMITTER: Pragyandipta P

PROVIDER: S-EPMC9829942 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Development of 9-(N-arylmethylamino) congeners of noscapine: the microtubule targeting drugs for the management of breast cancer.

Pragyandipta Pratyush P Naik Manas Ranjan MR Bastia Banajit B Naik Pradeep Kumar PK

3 Biotech 20230109 2

Noscapine is a natural lead molecule with anticancer activity at a higher concentrations. So, there is an urge for the development of more potent derivatives of noscapine. In this study, we have approached for development of 9-N-arylmethylamino derivatives of noscapine that kills cancer cells without affecting the normal cells. They were designed by substituting N-aryl methyl pharmacophore at the C-9 position and screened out top-ranked three derivatives 13a-c using molecula ...[more]

PMID: 36636578

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Project description:BackgroundMicrotubule drugs are effective anti-cancer agents, primarily due to their ability to induce mitotic arrest and subsequent cell death. However, some cancer cells are intrinsically resistant or acquire a resistance. Lack of apoptosis following mitotic arrest is thought to contribute to drug resistance that limits the efficacy of the microtubule-targeting anti-cancer drugs. Genetic or pharmacological agents that selectively facilitate the apoptosis of mitotic arrested cells present opportunities to strengthen the therapeutic efficacy.Methodology and principal findingsWe report a natural product Celastrol targets tubulin and facilitates mitotic cell death caused by microtubule drugs. First, in a small molecule screening effort, we identify Celastrol as an inhibitor of neutrophil chemotaxis. Subsequent time-lapse imaging analyses reveal that inhibition of microtubule-mediated cellular processes, including cell migration and mitotic chromosome alignment, is the earliest events affected by Celastrol. Disorganization, not depolymerization, of mitotic spindles appears responsible for mitotic defects. Celastrol directly affects the biochemical properties of tubulin heterodimer in vitro and reduces its protein level in vivo. At the cellular level, Celastrol induces a synergistic apoptosis when combined with conventional microtubule-targeting drugs and manifests an efficacy toward Taxol-resistant cancer cells. Finally, by time-lapse imaging and tracking of microtubule drug-treated cells, we show that Celastrol preferentially induces apoptosis of mitotic arrested cells in a caspase-dependent manner. This selective effect is not due to inhibition of general cell survival pathways or mitotic kinases that have been shown to enhance microtubule drug-induced cell death.Conclusions and significanceWe provide evidence for new cellular pathways that, when perturbed, selectively induce the apoptosis of mitotic arrested cancer cells, identifying a potential new strategy to enhance the therapeutic efficacy of conventional microtubule-targeting anti-cancer drugs.

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Development of 9-(N-arylmethylamino) congeners of noscapine: the microtubule targeting drugs for the management of breast cancer.

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Development of 9-(<i>N</i>-arylmethylamino) congeners of noscapine: the microtubule targeting drugs for the management of breast cancer.

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