Synthesis and Bioactivity of Novel Adamantyl Derivatives as Potent MDR Reversal Agents

Abstract

Multidrug Resistance (MDR) is a type of resistance of tumor cells to various kinds of chemotherapeutic drugs which are structurally unrelated and also one of the major impediments to chemotherapeutic treatment of cancer. It has been reported that 49 ATP-binding cassette (ABC) transporter genes are present in the human genome. Among them, over-expression of P-glycoprotein (P-gp), encoded by MDR1 gene is one of the major factors contributing to multidrug resistance which leads to barrier to successful chemotherapy. Therefore the availability of safe and potent MDR reversal agents would be beneficial for clinical use. Reversal agents can act by binding to the membrane transport protein (P-gp), by inhibiting MDR’s drug efflux capacity, or by suppressing expression of the MDR1 gene itself. Although a number of P-gp inhibitors have been developed, there is currently no clinically useful drug that inhibits P-gp. In an attempt to find new and more effective MDR reversal agents, we previously identified adamantyl derivatives exhibiting more potent MDR reversal activity than verapamil, a well-known P-gp inhibitor, without considerable intrinsic cytotoxicity. Compounds 1-2 were identified utilizing high throughput image-based DIOC2 efflux assays and anti-proliferation assays in a P-gp over-expressing MDR sarcoma cell line, MES-SA/DX5. Herein we describe a further structure-activity relationship study to find additional compounds in this series. With the objective of investigating the effect of aminebased substituents on reversal activity, we synthesized a series of adamantyl derivatives 2a-t that feature reductive amination of the adamantyl aldehyde derivatives as a key step. The synthetic procedures for 2a-t are described in Schemes 1 to 3. Synthesis of a new series of adamantyl derivatives (2a-t) were carried out starting from commercially available 3amino benzoic acid 3 (Scheme 1). The corresponding esters (4a-d) and amides (4e-g) of 3-amino benzoic acid were prepared in the next step. Further alkylation with chloroacetyl chloride resulted in the alkylated derivatives (5a-g). Bromination of 1-adamantane carboxylic acid 6 with bromine gave an intermediate 7, which was followed by Friedel-Crafts alkylation with anisole to provide compound 8, as shown in Scheme 2. Esterification of 8 resulted in compound 9, which was reacted with LiAlH4 to give an alcohol 10. The aldehyde 11 was then obtained by oxidation of alcohol 10. Demethylation of 11 was carried out by using BBr3 to afford a phenol compound 12, which was utilized as a key intermediate to prepare the final compounds. Adamantyl aldehyde 13, a precursor for the synthesis of the target adamantyl motifs (2a-n), was generated by reacting 12 with methyl 3-(2chloroacetamido) benzoate 5a. In similar fashion, the precursor 14o-t was generated by reacting 12 with 5b-g for the synthesis of derivatives 2o-t. Finally the reductive amination reaction of 13 or 14o-t with a variety of amine resulted in Pgp related MDR modulators 2a-t. Reversal activity of these derivatives was evaluated in