Unusual Reactivity of a Potent Platinum–Acridine Hybrid Antitumor Agent

Abstract

The formation of unusual seven-membered, sterically overloaded chelates [Pt(en)(L/L´)](NO3)2 (4a/4b) from the corresponding potent hybrid antitumor agents [PtCl(en)(LH/L´H)](NO3)2 (3a/3b) is described, where en is ethane-1,2-diamine and L(H) and L´(H) are (protonated) N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide and N-(2-(acridin-9-ylamino)ethyl)-N-methylacetimidamide, respectively. Compounds 3a and 3b inhibit H460 lung cancer cell proliferation with IC50 values of 12 ± 2 nM and 2.8 ± 0.3 nM, respectively. The new derivative 3b proves to be not only the most cytotoxic platinum–acridine hybrid of this kind, but also one of the most potent platinum-based anticancer agents described to date. The chelates 4a and 4b do not undergo ligand substitution reactions with nucleobase nitrogen and cysteine sulfur and do not intercalate into DNA. Despite their inertness, the two chelates appear to maintain micromolar activity in H460 cells. The results are discussed in the context of potential DNA-mediated and DNA-independent cell kill mechanisms and the potential use of the chelates as prodrugs.

Synthesis, Aqueous Reactivity, and Biological Evaluation of Carboxylic Acid Ester-Functionalized Platinum–Acridine Hybrid Anticancer Agents

“…This was unexpected since it has previously been observed that addition of steric bulk in this part of the molecule results in a decrease in cytotoxicity. 11 Another critical trend observed across the entire data set is that the hybrids in which the platinum moiety is separated from the intercalator by an extended propylene linker ( m = 3 in 9 and 12 ) show greatly reduced cell kill potential. For instance, in NCI-H460, derivatives 3´ and 11 (with m = 2) are approximately 6 times more cytotoxic than compounds 9 and 12 .…”

“…11 These ligands proved to be extremely labile, which resulted in undesired intramolecular substitution of the oxygen donor by the 9-amino group of the acridine moiety to produce a substitution-inert, marginally cytotoxic nitrogen chelate. We reasoned that incorporation of the carboxylato ligand as a pendant group into a chelate, similar to the dicarboxylato leaving group in the clinical drug carboplatin, 1 should produce a more stable, but yet DNA reactive entity.…”

“…11, 12 Three ester-modified hybrids (compounds 10 – 12 ) and, for comparison, two simple propionamidine derivatives ( 3´ and 9 ) were synthesized and isolated as mononitrate salts (Scheme 2) (Note: compound 3´ is the +1 charged form of compound 3 ). While compounds 3´ , 9 , 11 , and 12 were isolated in >85% yield and >95% analytical purity, the synthesis of derivative 10 suffered from an inherent instability of precursor complex 5 (decarboxylation, dimerization) as a consequence of the reactivity of the methylcyanoacetate ligand (see Supporting Information).…”

“…10 Specifically, compound 3 (Chart 1), generated by replacement of the thiourea in 2 (PT-ACRAMTU) with an amidine donor, and related derivatives have demonstrated a cytotoxic enhancement relative to cisplatin of up to 500-fold in NSCLC cell lines. 11, 12 Compound 3 produces significantly higher intracellular concentrations and DNA adduct levels in NCI-H460 cells than cisplatin, 13 and the hybrid adduct itself proves to be a significantly more severe form of DNA damage than the common bifunctional cross-link. 14 The cumulative effect of these pharmacological parameters renders the hybrid agent an efficient inhibitor of DNA replication and inducer of cell death.…”

Design, Synthesis and Biological Evaluation of Novel Rapamycin Benzothiazole Hybrids as mTOR Targeted Anti-cancer Agents

“…Additionally, benzothiazole has been an attractive pharmacological scaffold present in anti-cancer drugs, such as phosphatidyl inositol inhibitor 23,24) it is reasonable to combine benzothiazole with rapamycin nucleus to form a single molecular framework. 25,26) Through above mentioned molecular hybridization and bioisosterism process, it will be possible to obtain novel rapamycin derivatives with better anti-cancer activity with increasing bioavailability and better pharmacokinetics properties.…”