Optimization of the Synthesis of Antitumor Agent NSC260594 and related Derivatives

(E)-4-((1-methyl-6-nitroquinolin-4(1H)-ylidene)amino)-N-(4-((1-methylpyridin-4(1H)-ylidene)amino)phenyl)benzamide, also known as NSC260594 or XMH95, is a compound from the National Cancer Institute (NCI) Diversity Sets II, V and VII libraries characterized by an extended framework of four 4-substituted aromatic rings. This molecule emerged as a potential protein and nucleic acid binder with promising applications primarily in microbiology and as antitumor agent against two rare and aggressive malignancies: triple negative breast cancer (TNBC) and leiomyosarcoma (LMS). This thesis focuses on the definition of an optimal reaction sequence for the synthesis of NSC260594, which has not been precedingly reported in the literature, and could allow a better evaluation of the compound’s biochemical properties. The adopted strategy includes the formation of the central aromatic amide by protection of one amine group of 1,4-phenylenediamine, coupling of the remaining free amine with p-nitrobenzoic acid and nucleophilic aromatic substitution (SNAr) of the central unit with 4-halogenated heterocycles derivatives, yielding the complete molecular backbone. This synthetic strategy is attempted through two different pathways, developing the backbone toward either the quinoline or the pyridine first and methylating the heterocyclic nitrogens prior to and following SNAr reactions. The target molecule is obtained through a final N-H deprotonation and tautomerization. Due to NSC260594 poor solubility, this work also aims to synthesize a series of modified derivatives introducing a carboxylic derivative (acid or ester) onto the methyl group attached to the pyridinyl moiety. This modification enables subsequent conjugation with a short peptide sequence to enhance aqueous solubility and selective cellular uptake.