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

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Dec 11

PMID 38075843

Authors

Zahra Davarzani

Peyman Salehi

S Mohsen Asghari

Morteza Bararjanian

Ali Hamrahi Mohsen

Helia Dehghan Harati

Affiliations

Soon will be listed here.

Abstract

Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy, alongside cotarnine, a tetrahydroisoquinoline (THIQ) scaffold produced by the oxidative degradation of noscapine, has exhibited antitumor activities against several types of cancer. Although derivatization with amino acids is regarded as a promising strategy to improve chemotherapeutics' anticancer properties, amino acid conjugates of noscapine and cotarnine have been the least investigated. In the present study, 20 amino acid conjugated derivatives of noscapine and cotarnine at the 6-position were synthesized and evaluated for anticancer activity in both in vitro and in vivo conditions. Analysis of the antiproliferative activity against 4T1 mammary carcinoma tumor cells showed that compounds (noscapine-phenylalanine), (noscapine-tryptophan), and (cotarnine-tryptophan) with IC values of 11.2, 16.3, and 54.5 μM, respectively, were found to be far more potent than noscapine (IC = 215.5 μM) and cotarnine (IC = 575.3 μM) and were consequently opted for further characterization. Annexin V and propidium iodide staining followed by flow cytometry demonstrated improved apoptotic activity of compounds , , and compared to those of noscapine and cotarnine. In a murine model of 4T1 mammary carcinoma, noscapine-tryptophan inhibited tumor growth more effectively than noscapine and the other amino acid conjugates without adverse effects. Moreover, molecular docking studies conducted on tubulin as the intracellular target of noscapine suggested a good correlation with experimental observations. Based on these results, noscapine-tryptophan could be a promising candidate for further preclinical investigations.

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References

Cheriyamundath S, Mahaddalkar T, Nagireddy P, Sridhar B, Kantevari S, Lopus M . Insights into the structure and tubulin-targeted anticancer potential of N-(3-bromobenzyl) noscapine. Pharmacol Rep. 2018; 71(1):48-53. DOI: 10.1016/j.pharep.2018.09.002. View

Harikandei K, Salehi P, Ebrahimi S, Bararjanian M, Kaiser M, Khavasi H . N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study. Bioorg Chem. 2019; 91:103116. DOI: 10.1016/j.bioorg.2019.103116. View

Khan A, Suresh Kumar G . Natural isoquinoline alkaloids: binding aspects to functional proteins, serum albumins, hemoglobin, and lysozyme. Biophys Rev. 2017; 7(4):407-420. PMC: 5418488. DOI: 10.1007/s12551-015-0183-5. View

Checchi P, Nettles J, Zhou J, Snyder J, Joshi H . Microtubule-interacting drugs for cancer treatment. Trends Pharmacol Sci. 2003; 24(7):361-5. DOI: 10.1016/S0165-6147(03)00161-5. View

Fang L, Wang M, Gou S, Liu X, Zhang H, Cao F . Combination of amino acid/dipeptide with nitric oxide donating oleanolic acid derivatives as PepT1 targeting antitumor prodrugs. J Med Chem. 2014; 57(3):1116-20. DOI: 10.1021/jm401634d. View

Bentley K . beta-Phenylethylamines and the isoquinoline alkaloids. Nat Prod Rep. 1989; 6(4):405-32. DOI: 10.1039/np9890600405. View

Bennani Y, Gu W, Canales A, Diaz F, Eustace B, Hoover R . Tubulin binding, protein-bound conformation in solution, and antimitotic cellular profiling of noscapine and its derivatives. J Med Chem. 2012; 55(5):1920-5. DOI: 10.1021/jm200848t. View

Guo W, Zhang H, Yan W, Liu Y, Zhou F, Cai D . Design, synthesis, and biological evaluation of ligustrazine - betulin amino-acid/dipeptide derivatives as anti-tumor agents. Eur J Med Chem. 2019; 185:111839. DOI: 10.1016/j.ejmech.2019.111839. View

Kumar S, Jaipuri F, Waldo J, Potturi H, Marcinowicz A, Adams J . Discovery of indoximod prodrugs and characterization of clinical candidate NLG802. Eur J Med Chem. 2020; 198:112373. DOI: 10.1016/j.ejmech.2020.112373. View

10.

Han J, Konno H, Sato T, Soloshonok V, Izawa K . Tailor-made amino acids in the design of small-molecule blockbuster drugs. Eur J Med Chem. 2021; 220:113448. DOI: 10.1016/j.ejmech.2021.113448. View

11.

Capilla A, Soucek R, Grau L, Romero M, Rubio-Martinez J, Caignard D . Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties. Eur J Med Chem. 2018; 145:51-63. DOI: 10.1016/j.ejmech.2017.12.098. View

12.

Pingaew R, Mandi P, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V . Design, synthesis and molecular docking studies of novel N-benzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-based triazoles with potential anticancer activity. Eur J Med Chem. 2014; 81:192-203. DOI: 10.1016/j.ejmech.2014.05.019. View

13.

DeBono A, Capuano B, Scammells P . Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents. J Med Chem. 2015; 58(15):5699-727. DOI: 10.1021/jm501180v. View

14.

Singh I, Shah P . Tetrahydroisoquinolines in therapeutics: a patent review (2010-2015). Expert Opin Ther Pat. 2016; 27(1):17-36. DOI: 10.1080/13543776.2017.1236084. View

15.

Yang Z, Liu M, Peng X, Lei X, Zhang J, Dong W . Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro. Biochem Biophys Res Commun. 2012; 421(3):627-33. DOI: 10.1016/j.bbrc.2012.04.079. View

16.

DeBono A, Mistry S, Xie J, Muthiah D, Phillips J, Ventura S . The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents. ChemMedChem. 2013; 9(2):399-410. DOI: 10.1002/cmdc.201300395. View

17.

Nemati F, Bischoff-Kont I, Salehi P, Nejad-Ebrahimi S, Mohebbi M, Bararjanian M . Identification of novel anti-cancer agents by the synthesis and cellular screening of a noscapine-based library. Bioorg Chem. 2021; 115:105135. DOI: 10.1016/j.bioorg.2021.105135. View

18.

DeBono A, Xie J, Ventura S, Pouton C, Capuano B, Scammells P . Synthesis and biological evaluation of N-substituted noscapine analogues. ChemMedChem. 2012; 7(12):2122-33. DOI: 10.1002/cmdc.201200365. View

19.

Awasthi A, Kumar N, Mishra A, Ravi R, Dalal A, Shankar S . Noscapine-Amino Acid Conjugates Suppress the Progression of Cancer Cells. ACS Pharmacol Transl Sci. 2022; 5(12):1292-1304. PMC: 9745893. DOI: 10.1021/acsptsci.2c00172. View

20.

Liu M, Luo X, Liao F, Lei X, Dong W . Noscapine induces mitochondria-mediated apoptosis in gastric cancer cells in vitro and in vivo. Cancer Chemother Pharmacol. 2010; 67(3):605-12. DOI: 10.1007/s00280-010-1356-3. View