Noscapine–Amino Acid Conjugates Suppress the Progression of Cancer Cells

Abstract

Lung cancer is the leading cause of cancer deaths globally; 1 in 16 people are diagnosed with lung cancer in their lifetime. Microtubules, a critical cytoskeletal assembly, have an essential role in cell division. Interference with the microtubule assembly leads to genetic instability during mitosis and cancer cell death. Currently, available antimitotic drugs such as vincas and taxanes are limited due to side effects such as alopecia, myelosuppression, and drug resistance. Noscapine, an opium alkaloid, is a tubulin-binding agent and can alter the microtubule assembly, causing cancer cell death. Amino acids are fundamental building blocks for protein synthesis, making them essential for the biosynthesis of cancer cells. However, the ability of amino acids in drug transportation has yet to be exploited in developing noscapine analogues as a potential drug candidate for cancer. Hence, in the present study, we have explored the ninth position of noscapine by introducing a hydroxy­methylene group using the Blanc reaction and further coupled it with a series of amino acids to construct five target conjugates in good yields. The synthesized amino acid conjugate molecules were biologically evaluated against the A549 lung cancer cell line, among which the noscapine–tryptophan conjugate showed IC50 = 32 μM, as compared to noscapine alone (IC50 = 73 μM). Morphological changes in cancer cells, cell cycle arrest in the G1 phase, and ethidium bromide/acridine orange staining indicated promising anticancer properties. Molecular docking confirmed strong binding to tubulin, with a score of −41.47 kJ/mol with all 3D coordinates and significant involvement of molecular forces, including the hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations demonstrated a stable binding of noscapine–tryptophan conjugate for a prolonged time (100 ns) with the involvement of free energy through the reaction coordinates analyses, solving the bioavailability of parent noscapine to the body.

Inhibition of Myeloperoxidase Pro-Fibrotic Effect by Noscapine in Equine Endometrium

“…In fact, NOSC seems to have a dose-dependent effect. The effect of NOSC + tryptophan conjugate in human lung cancer cell lines caused cancer cell death in a dose-dependent manner [ 46 ]. Moreover, in breast cancer cell lines, NOSC showed a dose-dependent cytotoxic effect, presumably by the nuclear factor kappa-light-chain-enhancer of an activated B-cell (NF-kβ) pathway inhibition [ 36 ].…”

1,3‐Benzodioxole Tagged Lidocaine Based Ionic Liquids as Anticancer Drug: Synthesis, Characterization and In Silico Study

“…The third generation of ionic liquids is well known for biological activities such as anticancer, antifungal, antibacterial, and so on [31,32] . In last decade anticancer studies of imidazolium, phosphonium, chloine, benzalkonium, ammonium, and pyrrolidium‐based ionic liquids had been studied on different cancer cells like Hepatocarcinoma, Brain cancer cells, Human embryonic kidney, colon carcinoma, cervical cancer, melanoma [33–45] . Our research group has interest on development of third generation of ionic liquids as anti‐cancer drugs.…”

“…[31,32] In last decade anticancer studies of imidazolium, phosphonium, chloine, benzalkonium, ammonium, and pyrrolidium-based ionic liquids had been studied on different cancer cells like Hepatocarcinoma, Brain cancer cells, Human embryonic kidney, colon carcinoma, cervical cancer, melanoma. [33][34][35][36][37][38][39][40][41][42][43][44][45] Our research group has interest on development of third generation of ionic liquids as anti-cancer drugs. Hence, we have reported in-silico and in-vitro studies on tumor cell using derivatives of 1,3benzodioxole based ionic liquid.…”

Design, Synthesis, and Functional Studies on Noscapine and Cotarnine Amino Acid Derivatives as Antitumor Agents

“…They developed the noscapine−tryptophan conjugate as a possible antitumor compound to be assessed against the A549 lung cancer cell line. 22 In several previous reports, several noscapine analogues were developed by modification on its 6position. These derivatives were potential tubulin inhibitors and have shown better cytotoxic properties compared to noscapine.…”

“…Awasthi et al synthesized noscapine–amino acid conjugates by introducing amino acids at the 9-position of noscapine. They developed the noscapine–tryptophan conjugate as a possible antitumor compound to be assessed against the A549 lung cancer cell line . In several previous reports, several noscapine analogues were developed by modification on its 6-position.…”