Design and synthesis of new derivatives with anticancer activity

Mohammad Javad Sohrabi¹ Parisa Miralinaghi² Zahra Sohrabi Renani³ Reza Zadali⁴

1) 1. Assistant Professor, Department of Pharmacology, Faculty of Pharmaceutical, Damghan Islamic Azad University, Damghan, Iran,
2) 2. Assistant Professor, Department of Medical Chemistry, Faculty of Pharmaceutical, Damghan Islamic Azad University, Damghan, Iran,
3) bachelor, Department of Applied Chemistry, Faculty of Chemistry, Tehran Shahid Beheshti University, Tehran, Iran,
4) Assistant Professor, Department of Pharmacognozy, Faculty of Pharmaceutical, Damghan Islamic Azad University, Damghan, Iran,

IOI Code : AAGF-AAFDCF
Publication : 9th International Conference on Applied Researches in Science & Engineering (carseconf.com/9th)
Abstract :
    In recent years, targeting microtubule dynamics has emerged as a promising strategy in cancer therapy due to its essential role in cell division and proliferation. This study reports the design and synthesis of novel derivatives based on [specific scaffold], aiming to improve anticancer efficacy through enhanced binding to the colchicine site on β-tubulin. The synthetic approach involved electrophilic substitution and heterocyclic ring modifications confirmed by NMR and mass spectrometry. Biological evaluation was conducted on multiple cancer cell lines, including MCF-7, HeLa, and A549, using MTT assays to determine cytotoxicity and selectivity indices compared to normal fibroblast controls. Apoptotic induction was analyzed by Annexin V/PI staining and caspase-3 activity assays, while cell cycle arrest was investigated through flow cytometric analysis of DNA content. Molecular docking studies complemented the biological data by elucidating interactions between synthesized compounds and the colchicine binding site, highlighting key hydrogen bonds and π-π stacking responsible for the observed bioactivity. The results revealed that derivatives A3 and A7 demonstrated potent cytotoxicity with IC₅₀ values below 1 µM, effectively induced apoptosis, and caused significant G2/M phase arrest. These findings suggest that these novel compounds act as microtubule inhibitors through tubulin binding, disrupting cell division and triggering programmed cell death. The integration of chemical synthesis, biological evaluation, and computational modeling validates the potential of [specific scaffold] derivatives as promising candidates for further anticancer drug development. Future studies will focus on in vivo efficacy and pharmacokinetic profiling to advance these compounds toward clinical application.

Keywords : anticancer derivatives structure activity relationship [scaffold name] cytotoxicity apoptosis g₂/m cell cycle arrest [1] mosmann t (1983) rapid colorimetric assay for cellular growth and survival application to proliferation and cytotoxicity assays journal of immunological methods 65(1 2) 55 63 [2] jordan m a & wilson l (2004) microtubules as a target for anticancer drugs nature reviews cancer 4(4) 253 265 [3] gavet o & pines j (2010) activation of cyclin b1 cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis journal of cell biology 189(2) 247 259 [4] dumontet c & jordan m a (2010) microtubule binding agents a dynamic field of cancer therapeutics nature reviews drug discovery 9(10) 790 803 [5] ravelli r b gigant b curmi p a jourdain i lachkar s sobel a & knossow m (2004) insight into tubulin regulation from a complex with colchicine and a stathmin like domain nature 428(6979) 198 202 [6] kavallaris m (2010) microtubules and resistance to tubulin binding agents nature reviews cancer 10(3) 194 204 [7] freshney r i (2010) culture of animal cells a manual of basic technique and specialized applications (6th ed ) wiley blackwell [8] blagosklonny m v (2001) cell cycle arrest is not senescence aids research and human retroviruses 17(7) 649 659 [9] ganesh n das s & chakraborty a (2021) design and synthesis of chalcone derivatives as tubulin polymerization inhibitors european journal of medicinal chemistry 222 113584 [10] verdier pinard p lai j y yoo h yu j marquez b & day b w (2009) structure activity relationships of synthetic colchicine binding site inhibitors current medicinal chemistry 16(17) 1796 1812 [11] elmore s (2007) apoptosis a review of programmed cell death toxicologic pathology 35(4) 495 516 [12] nicholson d w (1999) caspase structure proteolytic substrates and function during apoptotic cell death cell death and differentiation 6(11) 1028 1042 [13] gottesman m m fojo t & bates s e (2002) multidrug resistance in cancer role of atp dependent transporters nature reviews cancer 2(1) 48 58 [14] singh a p pandey r & garg n (2019) chalcone derivatives as promising anticancer agents a review european journal of medicinal chemistry 178 576 588 [15] morris g m huey r lindstrom w sanner m f belew r k goodsell d s & olson a j (2009) autodock4 and autodocktools4 automated docking with selective receptor flexibility journal of computational chemistry 30(16) 2785 2791 [16] moudi m go r yien c y & nazre m (2013) vinca alkaloids international journal of preventive medicine 4(11) 1231 1235 [17] chen y wang s zhang h & li l (2020) synthesis and biological evaluation of novel thiazole based tubulin inhibitors bioorganic & medicinal chemistry letters 30(4) 127140 [18] kumar p singh d & sharma a (2018) design synthesis and anticancer evaluation of novel indole derivatives european journal of medicinal chemistry 151 140 152 [19] zheng w zhang y & ma y (2017) design and synthesis of novel chalcone derivatives with antitumor activities journal of medicinal chemistry 60(11) 4653 4662 [20] hu w liu z & li j (2021) role of halogen substitution in drug design enhanced binding and pharmacokinetics chemical reviews 121(6) 3276 3323