Authors: Byron Bennett1,
Van Vo2, Zeynep G.
Kabuloglu-Karayusuf2,
Stephen W. Carper2,
Vikas Sehdev1, Sara
Gilmore1, James C.K.
Lai1, Alok Bhushan1
Affiliation: (1)
Idaho State University and (2) University
of Nevada, Las Vegas
Title: 4,4¢-Disubstituted-2,2¢-bipyridine
Pt(II) Complexes: Cisplatin Analogues of Increased Cytotoxicity
Abstract: Cisplatin or
cis-diamminedichloridoplatinum(II)
(CDDP) is a platinum-containing chemotherapeutic drug widely used for treatment
of lung, head and neck, ovarian, bladder, and testicular carcinomas. For years
it has been effectively used in combination with other chemotherapeutic drugs to
treat a wide variety of cancers. However, drug- induced toxicity and development
of resistance to CDDP treatment has impeded its use over an extended period of
time for cancer treatment. Our study aims to address these limitations by
synthesizing novel CDDP derivatives with similar or better chemotherapeutic
efficacy and reduced toxicity. Reaction of (h4-1,5-cyclooctadiene)platinum(II)dichloride
with 4,4¢-(R)2-2,2¢-bipyridine
{where R = -OH, -OMe, -OEt, -O-iPr,
-O-sBu, -(CH2)3CF3,
-Et, -nPr, -nBu,
-tBu}
resulted in the isolation and spectroscopic characterization of (2,2’-bipyridinyl-κ2-N,N’)platinum(II)dichloride
complexes. The procedures for
preparing novel bipyridine starting materials are based on nucleophilic
substitution pathways featuring the appropriate resonance stabilized phenoxide
or benzylic carbanion. Anti-cancer efficacy of CDDP and its derivatives was
evaluated and compared on a wide spectrum of cancers by performing clonogenic
and cell survival assays on breast (MCF-7, MDA-MB-231, SK-BR-3), prostate
(DU-145), lung (A-549), and brain (U-87MC) cancer cell lines. Cell survival data
analysis of breast cancer cells treated with various concentrations of CDDP and
its derivatives (0.001-10µM)
indicate the following order of cell survival inhibition at 5µM
concentration for CDDP and its derivatives respectively: Breast cancer cells 1)
MDA-MB-231→ RGI089 (95.892±1.454)
< CDDP (34.190±0.500) <
RGI063 (13.177±0.808) < RGI0129
(4.237±0.286). 2) SK-BR-3→
RGI089 (89.094±0.821) < RGI063
(31.140±0.751) < CDDP (22.176±0.473)
< RGI0129 (8.8137±0.652). The
structure-activity relationship studies indicate the potential for novel
platinum compounds which may be beneficial as anticancer agents.