Stereochemistry of C-6 Nucleophilic Displacements on 1,1-Difluorocyclopropyldibenzosuberanyl Substrates. An Improved Synthesis of Multidrug Resistance Modulator LY335979 Trihydrochloride

Abstract

Studies of the displacement chemistry of 1,1-difluorocyclopropyldibenzosuberanyl alcohol 4 and its activated bromide derivative 6 have led to an improved approach to anti-2, a key precursor to LY335979 3HCl (1). Bromination of either syn-4 or anti-4 gave anti-oriented 6, indicating thermodynamically controlled product stereochemistry via a stabilized 1,1-difluorohomotropylium ion intermediate. Reaction of 6 with piperazine proceeded irreversibly to provide an isomeric mixture of piperazine products, with the syn:anti product ratio increased by solvent effects. Reaction of 6 with pyridine and pyrazine, on the other hand, gave anti-pyridinium and pyrazinium salts, respectively, apparently via equilibration of initially formed syn products. Reduction of pyrazinium salt 11 with lithium borohydride/TFA provided anti-2 unaccompanied by its syn isomer. A practical and expeditious approach to 1 was derived from these new results.

ATP-Binding Cassette B1 Transports Seliciclib (R-Roscovitine), a Cyclin-Dependent Kinase Inhibitor

“…Seliciclib (CYC202, R-roscovitine [2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine]) powder was kindly provided by the Institute de Chimie Organique, Université René Descartes, Paris, France (Hervé Galons). [(2R)-Anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline (LY335979) was synthesized as described previously (Barnett et al, 2004 Cell Lines. The chronic myeloid leukemia cell line, K562, and its ABCB1-overexpressing variant K562-MDR were received as kind gifts from Professor Balazs Sarkadi (National Blood Transfusion Service, Budapest, Hungary); MDCKII-MDR1, PLB985-BCRP (Kis et al, 2009), and parental cells were kindly provided by Dr. Katalin Német (National Blood Transfusion Service).…”

Zosuquidar and an albumin-binding prodrug of zosuquidar reverse multidrug resistance in breast cancer cells of doxorubicin and an albumin-binding prodrug of doxorubicin

“…Design of the albumin-binding prodrug of zosuquidar Zosuquidar was synthesized according to the literature [35]. For the design of the prodrug (see Scheme 1), we chose to introduce a maleimide linker incorporating an acid-sensitive hydrazone bond as this bond is stable after binding of the maleimide group to the cysteine-34 group of HSA and is cleaved in acidic conditions present in the extracellular environment of solid tumors as well as in the endosomes/lysosomes of tumor cells [26].…”

“…In this study, we show that zosuquidar as well as its acid-sensitive albumin conjugate were able to reverse MDR in two P-pg expressing breast cancer cells (MCF-7ADR and MT-3/ADR). Zosuquidar was obtained according to the literature in a 8-step synthesis resulting in 2 g of a light yellowish compound [35]. A solution of zosuquidar (1 equiv, 4 mmol, 625 mg) and triethylamine (6 equiv, 6 mmol, 815 ll) in dry dichloromethane (50 ml) was added to a solution of 4-acetylbenzoyl chloride [36] (6 equiv, 6 mmol, 1075 mg) in dry dichloromethane (25 ml).…”

Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

“…It was converted to ( R )-nosylate 15 in three steps by following a modified procedure [19], as shown in Scheme 2. The subsequent treatment with 5-hydroxyquinoline [20] led to the epoxide ( R )- 16 , serving as the chiral building bloc in the final key step, which involves the nucleophilic attack of the secondary amino group of the precursors 2b – 13b to the epoxide 16 , to deliver the final products 2a – 13a . The yields of the final coupling step are given in Scheme 2.…”