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5.1 Introduction
The membrane efflux protein P-glycoprotein, a member of the ATP binding cassette
(ABC) family, recognizes and transports structurally, chemically, and
armacologically diverse hydrophobic compounds, giving rise to a phenomenon known
as multidrug resistance (MDR). Development of MDR is one of the main reasons of
failure in cancer chemotherapy, as tumour cells, by increasing drug efflux, acquire
cross-resistance to many structurally and functionally unrelated anticancer agents,
which therefore never achieve effective intracellular concentrations 1 . In the past few
years, extensive studies have been performed with the aim of developing effective
chemo sensitizers to overcome MDR of human cancer cells. Potent P-glycoprotein
inhibitors have been tested in clinical trials so far, including Ca2+ channel blockers
such as verapamil and dihydropyridines 2,3 . However, clinical application of these
agents has not been extensively pursued to date, owing to their unwanted and
sometimes life threatening cardiovascular side effects such as atria-ventricular block
and hypotension. As a consequence, in the last few years, much attention has been
focused on congeners of these first generation-MDR inhibitors, in order to develop
compounds characterized by appropriate potency and selectivity but also by reduced
cardiovascular toxicity.
Very recently, 3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine
(DP7) was proposed as a new MDR reverter. It was found that DP7, at a
concentration two order of magnitude higher than its IC50 as a P-glycoprotein
inhibitor, was devoid of cardiovascular effects in in vitro rat preparations 4,5 . These
data were not considered sufficient evidence of DP7 safety before this drug could be
subjected to clinical investigation. Several 1,4 dihydropyridine calcium antagonists
are substrate of CYP enzymes. In particular, CYP3A4 metabolizes dihydropyridines
into the corresponding pyridines 6 . The dihydropyridine can also inhibit the activity of
CYP3A4. For example, Katoh 7 reported that nicardipine, benidipine, maidipine and
barnidipine strongly inhibited human CYP3A4 activity, while nivaldipine, nifedipine,
nitrendepine and amlodipine exhibited a weak inhibition.
The DP-7 was very well explored for variety of biological activity 8 . It was very
important to study the X-ray Crystal structure of this molecule which was not studied