Synthesis, in Vitro Anti-Breast Cancer Activity, and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3‘-Azido-3‘-deoxythymidine (AZT)

Abstract

We report the synthesis and anticancer activity of a series of AZT phosphoramidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.

Anti-Cancer Pyrimidines in Diverse Scaffolds: A Review of Patent Literature

“…Pyrimidine ring is the building unit of DNA and RNA, due to which pyrimidine derivatives exhibit diverse pharmacological activities such as anticancer [2][3][4][5][6][7][8][9][10], antiviral [11][12][13] especially anti-HIV [14][15][16], antimalarial [17][18][19], antimicrobial [20,21] and anti-inflammatory [22,23]. They also exhibit activity against gonadotropin releasing hormone receptors and display herbicidal potential by inhibiting acetohydroxyacid synthase, a key enzyme in the biosynthesis of branched-chain amino acids [24][25][26].…”

“…Diamino-6,7-dihydro-5H-pyrolo[2,3]pyrimidine derivative.in vitro endothelial capillary formation assay was also performed with Human umbilical vein endothelial cells (HU-VEC) and compound (124) inhibited Fibrinoblast Growth Factor induced capillary formation in dose dependent manner.Xiao et al filed a patent on 2,4'-diamino-6,7-dihydro-5H-pyrolo[2,3]pyrimidine derivatives as Focal Adhesion Kinases (FAK/Pyk2) inhibitors for treatment of FAK/Pyk2 mediated proliferative disease or disorder. Most of the synthesized compounds were potent and having IC 50 value less than 20nM against FAK and Pyk2.…”

Synthesis and Cytotoxic Activity of Steroidal Phosphorothioate,Phosphoroselenoate, and Phosphate Derivatives Conjugated with 3-Azido-3-Deoxythymidine

“…Many H-phosphonates of AZT were shown to possess high anti-HIV activity [5], such as PZT (5´-hydrogenphosphate of AZT) [6]. Recently, the prodrugs of AZT targeted in antitumor activity have been developed, such as phosphoramidate monoesters, ether phospholipids, and 5'-O-esters of AZT with three different inactive steroidal 17-carboxylic acids [7][8][9].…”

Biolabile constructs for pronucleotide design

“…Regarding the first strategy, a specific enzymatic system is needed to perform bioconversion of the structurally modified phosphorylated precursor. This strategy could be illustrated by the design of nucleoside fluorophosphate [5,6] or phosphoramidate [7,8] derivatives. In the second strategy, the hydrolysis of the phosphate-masking group bond requires a difference between the hydrolytic rates in the extra-and intracellular media, and involves either a specific chemical or an enzyme-mediated process.…”