New 1,2,3-triazole Linked Ciprofloxacin-chalcones Induce DNA Damage by Inhibiting Human Topoisomerase I& II and Tubulin Polymerization

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2022 May 13

PMID 35548854

Authors

Hamada H H Mohammed

Amer Ali Abd El-Hafeez

Kareem Ebeid

Aml I Mekkawy

Mohammed A S Abourehab

Emad I Wafa

Suhaila O Alhaj-Suliman

Aliasger K Salem

Pradipta Ghosh

Gamal El-Din A Abuo-Rahma

Alaa M Hayallah

Samar H Abbas

Affiliations

Soon will be listed here.

Abstract

A series of novel 1,2,3-triazole-linked ciprofloxacin-chalcones were synthesised as potential anticancer agents. Hybrids exhibited remarkable anti-proliferative activity against colon cancer cells. Compounds displayed ICs ranged from 2.53-8.67 µM, 8.67-62.47 µM, and 4.19-24.37 µM for HCT116, HT29, and Caco-2 cells; respectively, whereas the doxorubicin, showed IC values of 1.22, 0.88, and 4.15 µM. Compounds and were the most potent against HCT116 with IC values of 3.57, 4.81, 4.32, 4.87, and 2.53 µM, respectively, compared to doxorubicin (IC = 1.22 µM). Also, hybrids and exhibited remarkable inhibitory activities against topoisomerase I, II, and tubulin polymerisation. They increased the protein expression level of γH2AX, indicating DNA damage, and arrested HCT116 in G2/M phase, possibly through the ATR/CHK1/Cdc25C pathway. Thus, the novel ciprofloxacin hybrids could be exploited as potential leads for further investigation as novel anticancer medicines to fight colorectal carcinoma.

Citing Articles

Mechanistic Approach into 1,2,3-triazoles-based IIIM(S)-RS98 Mediated Apoptosis in Lung Cancer Cells.

Dolkar R, Paudwal G, Singh D, Behera C, Malik S, Ali S AAPS J. 2025; 27(1):35.

PMID: 39900819 DOI: 10.1208/s12248-025-01018-9.

Therapeutic potential of chalcone-1,2,3-triazole hybrids as anti-tumour agents: a systematic review and SAR studies.

Priya S, Islam M, Kasana S, Kurmi B, Gupta G, Patel P Future Med Chem. 2025; 17(4):449-465.

PMID: 39886772 PMC: 11834451. DOI: 10.1080/17568919.2025.2458450.

From Infection to Tumor: Exploring the Therapeutic Potential of Ciprofloxacin Derivatives as Anticancer Agents.

Hassan H, Hassan R, Elmagzoub R, Al-Emam A, Kossenas K, Abdel-Samea A Pharmaceuticals (Basel). 2025; 18(1).

PMID: 39861135 PMC: 11768150. DOI: 10.3390/ph18010072.

Design, Synthesis, Anticancer Screening, and Mechanistic Study of Spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide Derivatives.

El-Saghier A, Hashem H, Maher S, Enaili S, Alkhammash A, Brase S Int J Mol Sci. 2025; 26(2).

PMID: 39859577 PMC: 11766273. DOI: 10.3390/ijms26020863.

Indole Derivatives: A Versatile Scaffold in Modern Drug Discovery-An Updated Review on Their Multifaceted Therapeutic Applications (2020-2024).

Mo X, Rao D, Kaur K, Hassan R, Abdel-Samea A, Farhan S Molecules. 2024; 29(19).

PMID: 39407697 PMC: 11477627. DOI: 10.3390/molecules29194770.

References

Singh P, Anand A, Kumar V . Recent developments in biological activities of chalcones: a mini review. Eur J Med Chem. 2014; 85:758-77. DOI: 10.1016/j.ejmech.2014.08.033. View

Morphy R, Rankovic Z . Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005; 48(21):6523-43. DOI: 10.1021/jm058225d. View

Bonandi E, Christodoulou M, Fumagalli G, Perdicchia D, Rastelli G, Passarella D . The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov Today. 2017; 22(10):1572-1581. DOI: 10.1016/j.drudis.2017.05.014. View

Emami S, Ghobadi E, Saednia S, Hashemi S . Current advances of triazole alcohols derived from fluconazole: Design, in vitro and in silico studies. Eur J Med Chem. 2019; 170:173-194. DOI: 10.1016/j.ejmech.2019.03.020. View

Abdel-Aal M, Abdel-Aziz S, Shaykoon M, Abuo-Rahma G . Towards anticancer fluoroquinolones: A review article. Arch Pharm (Weinheim). 2019; 352(7):e1800376. DOI: 10.1002/ardp.201800376. View

Sissi C, Palumbo M . The quinolone family: from antibacterial to anticancer agents. Curr Med Chem Anticancer Agents. 2003; 3(6):439-50. DOI: 10.2174/1568011033482279. View

Worrell B, Malik J, Fokin V . Direct evidence of a dinuclear copper intermediate in Cu(I)-catalyzed azide-alkyne cycloadditions. Science. 2013; 340(6131):457-60. PMC: 3651910. DOI: 10.1126/science.1229506. View

Ashour H, Abou-Zeid L, El-Sayed M, Selim K . 1,2,3-Triazole-Chalcone hybrids: Synthesis, in vitro cytotoxic activity and mechanistic investigation of apoptosis induction in multiple myeloma RPMI-8226. Eur J Med Chem. 2020; 189:112062. DOI: 10.1016/j.ejmech.2020.112062. View

Keepers Y, Pizao P, Peters G, Winograd B, Pinedo H . Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays for in vitro chemosensitivity testing. Eur J Cancer. 1991; 27(7):897-900. DOI: 10.1016/0277-5379(91)90142-z. View

10.

Azema J, Guidetti B, Korolyov A, Kiss R, Roques C, Constant P . Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or.... Eur J Med Chem. 2011; 46(12):6025-38. DOI: 10.1016/j.ejmech.2011.10.014. View

11.

Foroumadi A, Emami S, Rajabalian S, Badinloo M, Mohammadhosseini N, Shafiee A . N-Substituted piperazinyl quinolones as potential cytotoxic agents: structure-activity relationships study. Biomed Pharmacother. 2008; 63(3):216-20. DOI: 10.1016/j.biopha.2008.01.016. View

12.

Zimmermann G, Lehar J, Keith C . Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today. 2007; 12(1-2):34-42. DOI: 10.1016/j.drudis.2006.11.008. View

13.

El-Damasy A, Haque M, Park J, Shin S, Lee J, Kim E . 2-Anilinoquinoline based arylamides as broad spectrum anticancer agents with B-RAF/C-RAF kinase inhibitory effects: Design, synthesis, in vitro cell-based and oncogenic kinase assessments. Eur J Med Chem. 2020; 208:112756. DOI: 10.1016/j.ejmech.2020.112756. View

14.

Yan W, Xiangyu C, Ya L, Yu W, Feng X . An orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent. Invest New Drugs. 2019; 37(4):784-790. DOI: 10.1007/s10637-019-00737-z. View

15.

Gootz T, McGuirk P, Moynihan M, Haskell S . Placement of alkyl substituents on the C-7 piperazine ring of fluoroquinolones: dramatic differential effects on mammalian topoisomerase II and DNA gyrase. Antimicrob Agents Chemother. 1994; 38(1):130-3. PMC: 284408. DOI: 10.1128/AAC.38.1.130. View

16.

Wang J . Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002; 3(6):430-40. DOI: 10.1038/nrm831. View

17.

Mohammed H, Abuo-Rahma G, Abbas S, Abdelhafez E . Current Trends and Future Directions of Fluoroquinolones. Curr Med Chem. 2018; 26(17):3132-3149. DOI: 10.2174/0929867325666180214122944. View

18.

Abdel-Aziz M, Park S, Abuo-Rahma G, Sayed M, Kwon Y . Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity. Eur J Med Chem. 2013; 69:427-38. DOI: 10.1016/j.ejmech.2013.08.040. View

19.

Sinha S, Field J, Miller J . Use of substitute Nonidet P-40 nonionic detergents in intracellular tubulin polymerization assays for screening of microtubule targeting agents. Biochem Cell Biol. 2017; 95(3):379-384. DOI: 10.1139/bcb-2016-0141. View

20.

Perez R, Godwin A, Handel L, Hamilton T . A comparison of clonogenic, microtetrazolium and sulforhodamine B assays for determination of cisplatin cytotoxicity in human ovarian carcinoma cell lines. Eur J Cancer. 1993; 29A(3):395-9. DOI: 10.1016/0959-8049(93)90394-u. View