SYNTHESIS, STRUCTURAL CHARACTERIZATION, AND ANTITUMOR PROPERTIES OF ANOVEL CLASS OF LARGE-RING PLATINUM(II) CHELATE COMPLEXES INCORPORATING THE CIS-1,4-DIAMINOCYCLOHEXANE LIGAND IN A UNIQUE LOCKED BOAT CONFORMATION

The first two analogs 5a,b of a new class of neutral large-ring square -planar Pt(II) chelate complexes of the generic structure [Pt(cis-1,4- dach)X(2)] were synthesized via a refined technique, structurally char acterized by NMR (H-1, C-13, Pt-195), FAB mass spectrometry, and X-ray crystallography, and evaluated for antitumor activity in vitro and in vivo in sensitive and Pt-resistant murine leukemia cell systems. An X -ray crystal structure analysis confirmed that [Pt(cis-1,4-dach)malona te] 5b is monomeric and that the cis-1,4-diaminocyclohexane (dach) lig and is incorporated in a unique and previously unknown locked boat con formation. Complex 5b crystallized as colorless rectangular plates in the orthorhombic space group Pcmn with Z = 4 and the lattice parameter s alpha = 6.239(1) Angstrom, b = 9.965(2) Angstrom, and c = 18.437(4) Angstrom. Important structural parameters are Pt-0 = 2.024(5) Angstrom , Pt-N = 2.021(6) Angstrom, N-Pt-N = 100 degrees, and N-Pt-0 = 85 degr ees; R = 0.0515, R(w) = 0.0635. Antitumor results in murine tumor mode ls show that the parent molecule 5a (X(2) = 2 Cl) (a) is more dose pat ent than cisplatin against the leukemias and solid tumors examined. (b ) possesses significant activity against cisplatin-resistant leukemias , but exhibits partial cross-resistance with cisplatin, and (c) may po ssess a spectrum of activity different from that, of cisplatin. Antitu mor test results in vitro indicate that (a) 5a is at least equivalent to cisplantin in dose potency and effectiveness in the leukemia cell s ystems studied except in the [Pt(1,2-dach)Cl-2]-resistant L1210 cell l ine, (b) the cisplatin-resistant leukemia cell systems exhibit partial cross-resistance to 5a, (c) 5a possesses either comparable or greater cytotoxicity than the reference complexes, CI-973 (3) and bis(platinu m) complex 4, and (d) 5a is more effective (similar to 18-fold) than [ Pt(1R,2R-dach)Cl-2]2 in inhibiting growth in the Pt(1,2-dach)-resistan t L1210 cell line, suggesting that [Pt(cis-1,4-dach)Cl-2] is either no t recognized as or is not acting as a ''typical'' Pt(dach) complex. Th e encouraging antitumor activity of 5a, coupled with a 10-fold higher aqueous solubility compared to [Pt(1R,2R-dach)Cl-2] 2 warrants the fol lowing future studies: synthesis of selected analogs, elucidating the nature of Pt-DNA binding sites, the mechanism of action, and the mecha nistic basis for the lack of cross-resistance of [Pt(cis-1,4-dach)Cl-2 ] against the [Pt(1,2-dach)Cl-2]-resistant L1210