The cytotoxic complex, [PtCl(Am) 2 (ACRAMTU)](NO 3 ) 2 (1) ((Am) 2 = ethane-1,2-diamine, en; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea), is a dual platinating/ intercalating DNA binder that, unlike clinical platinum agents, does not induce DNA cross-links. Here, we demonstrate that substitution of the thiourea with an amidine group leads to greatly enhanced cytotoxicity in H460 non-small cell lung cancer (NSCLC) in vitro and in vivo. Two complexes were synthesized: 4a (Am 2 = en) and 4b (Am = NH 3 ), in which N- [2-(acridin-9-ylamino) ethyl]-N-methylpropionamidine replaces ACRAMTU. Complex 4a proves to be a more efficient DNA binder than complex 1 and induces adducts in sequences not targeted by the prototype. Complexes 4a and 4b induce H460 cell kill with IC 50 values of 28 and 26 nM, respectively, and 4b slows tumor growth in a H460 mouse xenograft study by 40% when administered at a dose of 0.5 mg/kg. Compound 4b is the first non-cross-linking platinum agent endowed with promising activity in NSCLC.
Platinum-acridine conjugates were prepared from [PtCl2(ethane-1,2-diamine)] and the novel acridinylthioureas MeHNC(S)NMeAcr (6) and MeHNC(S)NMe(CH2CH2)NHAcr (15) by replacing one chloro leaving group in the cisplatin analogue with thiourea sulfur. In HL-60 leukemia cells, IC(50) values for 7 (Pt-tethered 6) and 16 (Pt-tethered 15) were 75 and 0.13 microM, respectively. In the ovarian cell lines 2008 and C13, 16 was active at micromolar concentrations and showed only partial cross-resistance with clinical cisplatin. Possible structure-activity relationships are discussed.
89Zr–Tetraazamacrocycle complexes display extraordinary stability.
Recent observations that several trans-platinum complexes exhibit antitumor activity including activity in cisplatin-resistant tumor cells, violates the classical structure/activity relationships of platinum(II) complexes. According to these relationships, only bifunctional platinum(II) complexes with cis-oriented leaving ligands should be therapeutically active. In order to contribute to the understanding of mechanisms underlying the antitumor activity of these new trans-platinum analogs, various biochemical and biophysical methods as well as molecular modeling techniques were employed to study the modifications of DNA by antitumor trans-[PtCl 2(NH3)(quinoline)]. The results indicated that trans-[PtCl2(NH3)(quinoline)] coordinated monofunctionally to DNA with a similar rate as transplatin. The overall rate of the rearrangement to bifunctional adducts was also similar to that observed in the case of DNA modification by transplatin, i.e. it was relatively slow (after 48 h Ϸ34% adducts remained monofunctional). In contrast to transplatin, however, trans-[PtCl 2 (NH 3 )(quinoline)] formed considerably more interstrand cross-links after 48 h (Ϸ30%) with a much shorter half-time (Ϸ5 h) (Ϸ12% for transplatin, t 1/2 Ͼ 11 h). The results also suggested that the quinoline ligand in all or in a significant fraction of DNA adducts of trans-[PtCl 2 (NH 3 )(quinoline)], in which platinum is coordinated to base residues, was well positioned to interact with the duplex.The adducts of trans-[PtCl 2(NH3)(quinoline)] terminated in vitro RNA synthesis preferentially at guanine residues. Surprisingly, the type and extent of conformational alterations induced in DNA indicates that trans-[PtCl 2 (NH 3 )(quinoline)] behaves in some respects like cisplatin, as indicated by the fact that trans-[PtCl 2(NH3)(quinoline)]-modified DNA is recognized by cisplatin-specific antibodies. Models for both monofunctional adducts and bifunctional interstrand cross-links are proposed. Computer-generated AMBER models show that the combination of monofunctional covalent binding and a stacking interaction between quinoline and the DNA bases can produce a kink in the duplex which is strongly suggestive of the directed bend produced by the major cisplatin-DNA adduct (1,2 intrastrand cross-link). Unique DNA adducts of this type formed by trans-[PtCl 2 (NH 3 )(quinoline)] may contribute to the antitumor efficacy of this agent.Keywords : DNA ; platinum drug; quinoline; antitumor activity; conformation.The clinical use of cis-diamminedichloroplatinum(II) (cis-display novel clinical properties in comparison to the parent platin; Fig. 1) and cis-diammine (1,1-cyclobutanedicarboxylato)-drug [3]. This situation underlines the need for new classes of platinum(II) (carboplatin) in cancer chemotherapy is now well platinum complexes which may display better and/or alternative established. Early empirical structure/activity relationships of clinical activity in comparison to cisplatin and carboplatin. In order to explain the antitumor activity of these nonclassi- line)...
Nonclassical platinum-based antitumor agents have shown enormous potential in the treatment of chemoresistant cancers. The design of these agents is based on the hypothesis that platinum-containing pharmacophores that react with nuclear DNA in cancer cells radically differently than the clinical agent cisplatin will produce a unique spectrum of biological activity. One such class of molecules are platinum-acridine hybrid agents derived from the prototypical complex [PtCl(en)(ACRAMTU)](NO(3))(2), en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea ("PT-ACRAMTU"). This article summarizes milestones in the development of these agents and reviews critical key concepts that have guided their design and that of related compounds.
[PtCl(en)(ACRAMTU-S)](NO(3))(2) (PT-ACRAMTU; en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) is a dual metalating/intercalating DNA binding drug conjugate that shows cytotoxicity at micromolar to nanomolar concentrations in a wide range of solid tumor cell lines. In approximately 80% of its adducts, PT-ACRAMTU binds to guanine-N7 in the major groove, selectively at 5'-CG sites [Budiman, M. E. et al. (2004) Biochemistry 43, 8560-8567]. Here, we report the synthesis, physical characterization, and NMR solution structure of a site-specifically modified octamer containing this adduct, 5'-CCTCGTCC-3'/3'-GGAGCAGG-5', where the asterisk indicates the [Pt(en)ACRAMTU)](3+) fragment. The structure was determined by a combination of high-resolution 2-D NMR spectroscopy and restrained molecular dynamics/molecular mechanics (rMD/MM) calculations using 179 NOE distance restraints and refined to an r(6) weighted residual (R(x)) of 9.2 x 10(-)(2) using the complete relaxation matrix approach. An average structure was calculated from the final ensemble of 19 rMD geometries showing pairwise root-mean-square deviations of <1.05 A. The dual binding increases the thermal stability of the octamer compared to the unmodified duplex (DeltaT(m) = 13.2 degrees ). The modified sequence shows structural features reminiscent of both B- and A-type DNA. Watson-Crick hydrogen bonding is intact at and beyond the adduct site. Platinum is bound to the N7 position of G5 in the major groove, and ACRAMTU intercalates into the central 5'-C4G5/C12G13 base-pair step on the 5'-face of the platinated nucleobase. The chromophore's long axis is aligned with the long axes of the adjacent base pairs, maximizing intermolecular pi-pi stacking interactions. PT-ACRAMTU lengthens (rise, 6.62 A) and unwinds (twist, 15.4 degrees ) the duplex at the central base-pair step but does not cause helical bending. No C3'-endo deoxyribose pucker and no significant roll are observed at the site of intercalation/platination, which clearly distinguishes the PT-ACRAMTU-induced damage from the 1,2-intrastrand cross-link formed by cisplatin. Overall, the DNA perturbations produced by PT-ACRAMTU do not appear to mimic those caused by the major cisplatin lesion. Instead, intriguing structural similarities are observed for PT-ACRAMTU's monoadduct and the N7 adducts of dual major-groove alkylating/intercalating antitumor agents, such as the pluramycins.
The sequence specificity and time course of covalent DNA adduct formation of the novel platinum-acridine conjugate [PtCl(en)(ACRAMTU)](NO(3))(2) [PT-ACRAMTU, 2; en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea] have been investigated using restriction enzyme cleavage and transcription footprinting assays and compared to the damage produced by the clinical agent cis-diamminedichloroplatinum(II) (cisplatin, 1). The rate of DNA binding of 1 and 2 was also monitored by atomic emission spectrometry. Restriction enzymes were chosen that cleave the phosphodiester linkage at, or adjacent to, the predicted damage sites. While conjugate 2 selectively protected supercoiled plasmid from cleavage by EcoRI and DraI enzymes at their respective restriction sites, G downward arrow AATTC and TTT downward arrow AAA, 1 inhibited DNA hydrolysis by HindIII and PspOMI at A downward arrow AGCTT and G downward arrow GGCCC (arrows mark cleavage sites) more efficiently. Transcription footprinting using T7 RNA polymerase revealed major single-base damage sites for 2 at adenine in 5'-TA and 5'-GA sequences. In addition, the enzyme is efficiently stalled at guanine bases, primarily in the sequence 5'-CGA where the damaged nucleobase is flanked by two high-affinity intercalation sites of ACRAMTU. While 1 targets poly(G) sequences, the binding of 2 appears to be dominated by the groove and sequence recognition of the intercalator. The biochemical assays used confirm previous structural information extracted from mass spectra of DNA fragments modified by 2 isolated from enzymatic digests [Barry, C. G., et al. (2003) J. Am. Chem. Soc. 125, 9629-9637]. Possible DNA-binding mechanisms and biological consequences of the unprecedented modification of alternating TA sequences by 2, which occurred at a faster rate than binding to G, are discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.