Chiral Salicyl Diamines: Potent Anticancer Molecules

Abstract

A set of 12 enantiomeric diamine-based small molecules was synthesized and screened for anticancer activity against five human cancer cell lines: NCI-H460, A549, MCF-7, SK-BR-3, and T-47D. The salicyl diamino compounds (1-6) were found to induce inhibition of the growth of cancer cells at submicromolar concentrations. The lead compound, N,N'-bis-salicyl-(1R,2R)-diaminocyclohexane (1) displayed single-reagent anticancer activity with an IC(50) value equal to or less than 2.0 microM in H460 and A-549 cancer cells. SRB and colony formation assays indicated that compound 1 shows greater cytotoxic activity toward MCF-7 cells than MCF-10A cells. Real-time RT-PCR analysis demonstrated that compound 1, is an extremely efficient regulator of antiapoptotic genes, Bcl-xL, Bcl-2, and the cell cycle related gene, cyclin D1. This study provides a new insight into the development of novel small molecules in the treatment of human breast cancers.

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)3 Thymidine Complexes

“…In a different study, the IC 50 values of 5-fluorouracil and doxorubicin were determined to be 9.19 and 7.88 mm at 96 h, respectively. [48] Other metal-based anticancer agents are organometallic osmium(II) arene complexes with IC 50 values of 24 mm at 24 h and chloro half-sandwich osmium(II) complexes, with the most toxic complex possessing an IC 50 value of 6.4 mm at 24 h. [46,47,49] An alkenyl-substituted ansa-zirconocene complex showed moderate toxicity against A549 cells with an IC 50 value of 136.4 mm at 96 h. [50] An octaazacyclotetracosane dizinc(II) complex has been described as a potent inhibitor of tumor growth, and its IC 50 was determined to be 8.8 mm at 48 h. [51] In contrast, organic chiral salicyl diamines are potent anticancer molecules, with IC 50 values in the range of 0.8-1.8 mm at 48 h. [52] In this study, it was found that out of four different positions, conjugation of the rhenium chelate function to either position C5' of the ribose sugar or position N3 of the pyrimidine base resulted in the most potent organorhenium complexes. A general trend could be established in which an increase in toxicity could be achieved with increasing tether length between the biomolecule and the complex entity.…”

Study on Antitumor Platinum(II) Complexes of Chiral Diamines with Dicyclic Species as Steric Hindrance

“…The unique and potent antitumor activity of oxaliplatin is believed to be attributed to a [Pt(1R,2R-DACH)] 2+ unit that plays a pivotal role in increasing cell uptake and inhibiting DNA mismatch repair. 21,22 Although numerous platinum complexes of trans-1,2-DACH analogs have recently been studied to explore the sterically hindered platinum complexes, 23,24,25 only a few of platinum complexes of carrier ligands with dicyclic framework as steric hindrance were involved. So far, there are limited examples of such ligands involved in two types of (i) 1,2-diamine like 1,2-camphordiamine ( Figures 1A and 1B), 26 and (ii) 1,4-diamine like 1,2-bis(aminomethyl)carbobicyclic derivatives (Figures 1C and 1D).…”

Relationship Between Anticancer Activity and Stereochemistry of Saldach Ligands and their Iron(III) Complexes

“…We selected the oxidation state +III because an earlier study demonstrated nearly identical effects of iron(II) and iron(III) complexes. Furthermore, we also investigated the cytotoxicity of the free ligands, because Gao et al recently identified related chiral N,N9-bis-salicyl-1,2-diaminocyclohexane compounds as effective anticancer agents in the down regulation of Bcl-2-family gene expression in human breast cancer cells [9].…”