Charge Transfer-oxy Radical Mechanism for Anti-cancer Agents

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants

Synthesis of N-substituted 3,5-bis(arylidene)-4-piperidones with high antitumor and antioxidant activity

A series of 3,5-bis(arylidene)-4-piperidones (DAP compounds) are considered as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structureactivity relationship studies by synthesizing a number of 3,5-bis(arylidene)-4-piperidones Nalkylated or acylated with nitroxides or their amine precursors as potent antioxidant moieties. Both subtituents on arylidene rings and on piperidone nitrogen (five- or six-membered, 2- or 3- or 3,4-disubstituted, isoindoline nitroxides) were varied. The anticancer efficacy of the new DAP compounds was tested by measuring their cytotoxicity to cancer cell lines A2780 (human epithelial ovarian cancer cell line) and MCF-7 (human breast cancer cell line) and to H9c2, a noncancerous (healthy) cardiac cell line. The results showed that all DAP compounds induced a significant loss of cell viability in both the human cancer cell lines tested, however only pyrroline appended nitroxides (5c,1 5e, 7, 9) showed limited toxicity toward noncancerous cell lines. Computer docking simulations support the biological activity tested. These results suggest that antioxidant-conjugated DAPs will be useful as a safe and effective anticancer agent for cancer therapy

Vitamin B12 as a carrier for targeted platinum delivery: in vitro cytotoxicity and mechanistic studies

It is attractive to use vitamin B12 as a carrier for targeted delivery of cytotoxic agents such as platinum complexes owing to the high demand for vitamin B12 by fast proliferating cells. The basic {B12-CN-PtII} conjugates are recognized by intracellular enzymes and converted to coenzyme B12 in an enzymatic adenosylation assay. The reductive adenosylation of {B12-CN-PtII} conjugates leads to the release of the PtII complexes; thus, {B12-CN-PtII} conjugates can be considered as prodrugs. It is important not only to elucidate the activity of the cisplatin-B12 conjugates, but also to understand the mode of action on a molecular level. Chemical reduction of {B12-CN-PtII} conjugates with cobaltocene yielded cob(II)alamin and induced release of the corresponding PtII species. Kurnakov tests and coordination of 2′-deoxyguanosine or GMP to the released PtII complexes allowed isolation and characterization of PtII complexes as released during enzymatic adenosylation. The biological activity of these PtII complexes was evaluated. Since the cleaved PtII complexes show cytotoxicity, the {B12-CN-PtII} conjugates can be used for specific targeting of cancer cells and therapeutic drug delivery. Preliminary in vitro cytotoxicity studies indicated lower activity (IC50 between 8 and 88μM) than found for pure cisplatin. Since active transport and receptor-mediated uptake limits the intracellular {B12-CN-PtII} concentration, comparison with pure cisplatin is of limited use. We could show that the PtII complexes cleaved from B12 exerted a cytotoxicity comparable to that of cisplatin itself. Cytotoxicity studies in vitamin B12 free media showed a dependence on the addition of transcobalamin II for B12-Pt(II) conjugate

Cytotoxicity of Pyrazine-Based Cyclometalated (C^Npz^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties

The synthesis of a series of cyclometalated gold(III) complexes supported by pyrazine-based (C^N^C)-type pincer ligands is reported, including the crystal structure of a cationic example. The compounds provide a new platform for the study of antiproliferative properties of gold(III) complexes. Seven complexes were tested: the neutral series (C^Npz^C)AuX [X = Cl (1), 6-thioguanine (4), C≡CPh (5), SPh (6)] and an ionic series that included the N-methyl complex [(C^NpzMe^C)AuCl]BF4 (7) and the N-heterocyclic carbene complexes [(C^Npz^C)AuL]+ with L = 1,3-dimethylbenzimidazol-2-ylidene (2) or 1,3,7,9-tetramethylxanthin-8-ylidene (3). Tests against human leukemia cells identified 1, 2, 3, and 4 as particularly promising, whereas protecting the noncoordinated N atom on the pyrazine ring by methylation (as in 7) reduced the cytotoxicity. Complex 2 proved to be the most effective of the entire series against the HL60 leukemia, MCF-7 breast cancer, and A549 lung cancer cell lines, with IC50 values down to submicromolar levels, associated with a lower toxicity toward healthy human lung fibroblast cells. The benzimidazolylidene complex 2 accumulated more effectively in human lung cancer cells than its caffeine-based analogue 3 and the gold(III) chloride 1. Compound 2 proved to be unaffected by glutathione under physiological conditions for periods of up to 6 days and stabilizes the DNA G-quadruplex and i-motif structures; the latter is the first such report for gold compounds. We also show the first evidence of inhibition of MDM2–p53 protein–protein interactions by a gold-based compound and identified the binding mode of the compound with MDM2 using saturation transfer difference NMR spectroscopy combined with docking calculations

Not only P-glycoprotein: amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins

The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR