Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential

Abstract

Antiangiogenic agents (AA) are cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

“…15 , 33 In this study, we extend our original reports to the design, discovery and preclinical evaluation of 7-benzyl- N -substituted-pyrrolo[3,2- d ]pyrimidin-4-amines with MTA and triple angiokinase (VEGFR-2, PDGFR-β, EGFR) inhibitory activities in single molecules.…”

“…Our hybrid design to structurally engineer VEGFR-2 inhibitory activity into our existing MTA 1 afforded 3 , a single agent with potent activities against both VEGFR-2 and tubulin assembly. 15 Compound 3 reduced tumor size and vascularity in two flank xenograft models [the BLBC MDA-MB-435 and U251 glioma models] and in a 4T1 triple negative breast orthotopic allograft model, without overt toxicity to animals. 15 A structure-activity study suggested that the methyl group attached to the nitrogen bridge in the 4-position and the 4’-methoxy group in 3 were crucial for inhibition of tubulin and removal of either of these moieties resulted in a complete loss of the ability of the compound to inhibit tubulin assembly and also decreased VEGFR-2 inhibition in cells.…”

“…15 A structure-activity study suggested that the methyl group attached to the nitrogen bridge in the 4-position and the 4’-methoxy group in 3 were crucial for inhibition of tubulin and removal of either of these moieties resulted in a complete loss of the ability of the compound to inhibit tubulin assembly and also decreased VEGFR-2 inhibition in cells. 15 …”

“…The key intermediate 7-benzyl-4-chloro-2-methyl-5 H –pyrrolo[3,2- d ]pyrimidine 11 15 (Scheme 1) was synthesized from benzaldehyde as previously described. 15 Nucleophilic aromatic substitution reactions of 11 with appropriately substituted amines in isopropanol at reflux afforded compounds 4 and 5 in 76 and 79% yields, respectively.…”

Cu-Catalyzed Expeditious Synthesis of N-Benzylaminoheter-ocycles Using N-Tosylhydrazones and Aminoheteroarenes

“…[1] In recent past, various N-benzylaminoheterocycles such as Flupirtine, [2] Ferroquine, [3] aminothiazole derivative, [4] IMC-094332, [5] Tripelennamine [6] have been emerged as drug candidates (Figure 1). Besides medicinal uses, some of the Nbenzylamino-heterocycles have been proved to exhibit prominent applications in materials science.…”