Synthesis, characterisation and in vitro antitumour potential of novel Pt(II) estrogen linked complexes

Abstract

The Cu(I) alkyne azide click reaction of 17α-ethynylestradiol and di-tert-butyl (2-azidopropane-1,3-diyl)dicarbamate afforded the novel 1,4 disubstituted 1,2,3 triazole and estrogen-based ligand 2-(4-(estradiol)-1H-1,2,3-triazol-1-yl)propane-1,3-diamine, EDiolDap. Reaction of EDiolDap with Pt(II) DMSO precursors, cis-[PtCl 2 (DMSO) 2 ] and cis-[Pt(CBDCA)(DMSO) 2 ] gave the corresponding Pt(II) estrogen linked complexes [PtCl 2 (EDiolDap)] and [Pt(CBDCA)(EDiolDap)] respectively in good yield. Both Pt(II) estrogen linked complexes exhibited superior activity as compared to cisplatin and carboplatin in 2D culture and exhibited ca. 30 fold higher activity, in terms of IC 50 values, against ER+ cancer cells (cervical, breast and ovarian) as compared to the reference ER− colon cancer line. [PtCl 2 (EDiolDap)] and [Pt(CBDCA)(EDiolDap)] retained their anti-tumour activity in an ovarian 3D spheroid culture model and reduced the viability of ovarian cancer cell spheroids ca. 9fold and 5-fold better, respectively, as compared to cisplatin.

Anticancer activity, DNA binding and cell mechanistic studies of estrogen-functionalised Cu(II) complexes

“…In turn, a host of strategies have been employed to date where derivatives of one of the three major endogenous estrogens (estrone, estradiol, and estriol) have been chemically linked to a platinum-containing anticancer drug [36][37][38] and radiopharmaceuticals [39]. Recently, we reported the antimicrobial and anticancer activity of steroid derivatives of Cu(II), Pt(II), and Au(I) complexes containing both the female (estradiol) and male (testosterone) steroids [40][41][42]. Here, we present the syntheses, chemical and electrochemical investigation, the DNA binding and cleavage properties together with a detailed biological study of the anticancer activity on 2D and 3D cancer cell cultures of a series of estrogen-functionalized Cu(II) complexes with the general formula [Cu(N∩N)(estradiol-phen)](NO 3 ) 2 , where (N∩N) is phenanthroline, DPQ, DPPZ and DPPN (Fig.…”

A Click Chemistry Approach to Targeted DNA Crosslinking with cis‐Platinum(II)‐Modified Triplex‐Forming Oligonucleotides

“…2‐Azidopropane‐1,3‐diamine hydrochloride ( 4 ) was selected as a suitable bidentate ligand scaffold as it had been previously shown to be an efficient chelator for platinum while maintaining excellent click orthogonality. [16a] Although 5 and 7 have previously been reported in the development of diazenecarboxamide‐extended conjugates [17] — 5 in the identification of platinum cellular protein targets [18] and 7 further afield in mitochondrial localisation [19] and clicked estrogen‐hybrid generation [20] —we here extend this concept to the oxaliplatin‐like derivative 8 , which, to our knowledge, has not yet been reported. Additionally, no work has yet been performed to construct gene‐targeting hybrids involving azide‐Pt II and alkyne‐modified TFOs.…”

A Click Chemistry Approach to Targeted DNA Crosslinking with cis‐Platinum(II)‐Modified Triplex‐Forming Oligonucleotides

“…2-Azidopropane-1,3diamine hydrochloride (4)was selected as asuitable bidentate ligand scaffold as it had been previously shown to be an efficient chelator for platinum while maintaining excellent click orthogonality. [16a] Although 5 and 7 have previously been reported in the development of diazenecarboxamide-extended conjugates [17] -5 in the identification of platinum cellular protein targets [18] and 7 further afield in mitochondrial localisation [19] and clicked estrogen-hybrid generation [20] we here extend this concept to the oxaliplatin-like derivative 8,w hich, to our knowledge,h as not yet been reported. Additionally,n ow ork has yet been performed to construct gene-targeting hybrids involving azide-Pt II and alkyne-modified TFOs.All three target complexes were accessed through acommon ligand, di-tert-boc-2-hydroxy-1,3-diaminopropane,…”