Novel Water-Soluble Substituted Pyrrolo[3,2-d]pyrimidines: Design, Synthesis, and Biological Evaluation as Antitubulin Antitumor Agents

Abstract

Purpose To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents. Methods Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and displace colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel. Results Pyrrolo[3,2-d]pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound that was tested in the NCI 60 cell line is a 2-digit nanomolar (GI50) inhibitor of 8 tumor cell lines. Conclusion We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization.

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

“…However, compound 8 with added conformational restriction via a N5-methyl over 5 was highly potent and only 2-fold less potent than the most potent analog 7 . As with previously described pyrimidine fused bicyclic and tricyclic compounds, 15, 34, 48–50 the methyl group attached to the 4-nitrogen bridge is crucial for inhibition of tubulin assembly. Removal of this N -methyl group ( 6 compared with 7 ) resulted in significant loss of tubulin inhibitory activity.…”

“…1) containing the pyrrolo[3,2- d ]pyrimidine scaffold afforded potent MTAs. 34 The on-going clinical trials of antiangiogenic agents in combination with tumor-cytotoxic MTAs prompted the design and development of single agents with both VEGFR-2 and tubulin inhibitory activities. As an initial study we appended the 7-benzyl group, which dictates RTK inhibitory activity in substituted 7-benzyl pyrrolo[2,3- d ]pyrimidines of general structure 2 35 (Fig.…”

Microtubule targeting agents in glioma

“…In an effort to design antimitotic agents which can act on multiple targets on cancer cells and starting from the structural similarity of tubulin binding agents with receptor tyrosine kinase (RTK) inhibitors, Gangjee et al have designed several analogs of combretastatin A to potentially act as inhibitors of both microtubule dynamics and RTKs (49). The authors showed that compound 3-HCl (later called AG119), a water soluble derivate of pyrrolo [3,2-d] pyrimidine, previously reported to have antiangiogenic, antimetastatic, and antitumor activity (52), when modified to incorporate a benzyl group acquires anti VEGFR2 activity, comparable to sunitinib. This was documented in an in vitro assay of tyrosine phosphorylation following stimulation with VEGF.…”

Anticancer Properties of Halogenated Pyrrolo[3,2‐d]pyrimidines with Decreased Toxicity via N5 Substitution

“…These interesting heterocycles have shown activity as bactericides [1] , protozoicides [2] , and as anti-tumor agents through inhibition of a variety of enzymes including tubulin [3] , NEDD8-activating enzyme (NAE) [4] , and several kinases. [5, 6] However, the properties of these molecules that affect their pharmacokinetic profile is under-investigated.…”