Novel Combretastatin-2-aminoimidazole Analogues as Potent Tubulin Assembly Inhibitors: Exploration of Unique Pharmacophoric Impact of Bridging Skeleton and Aryl Moiety

Abstract

Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route involving atom economical arene C-H bond arylation. Interestingly, four compounds showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer cells much more efficiently than CA-4. It depolymerized microtubules, induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding of compound 12 to tubulin. The distinctive pharmacophoric features of the bridging motif as well as quinoline nucleus were explored. We noted also a valuable quality of compound 12 as a potential probe in characterizing new CA-4 analogues.

Lessons from bacterial homolog of tubulin, FtsZ for microtubule dynamics

“…This led to the identification of a new combretastatin-2-aminoimidazole analog having better efficacy than CA-4 (Fig. 4) (Chaudhary et al 2016). The compound exerts much stronger effects on microtubules than CA-4.…”

“…The failure of septation and division would thereby lead to cell death. Being one of the most highly conserved proteins in bacteria, inhibitors of FtsZ can be used as broad-spectrum antibiotics to target a wide range of pathogens (Rothfield et al 1999, Margolin 2000, Kapoor & Panda 2009, Singh et al 2012, Panda et al 2016. The structural and functional homology of tubulin and FtsZ provides a platform to explore the possibility of studying agents that target tubulin as FtsZ inhibitors or at least as potential leads for them.…”

“…Several compounds have been identified that target the GTP-binding site of FtsZ and thereby inhibit polymerization (Läppchen et al 2008, Chan et al 2013, Ruiz-Avila et al 2013, Panda et al 2016. A study using GTP analogs established several molecules to have potent anti-FtsZ activity, while some among them showed differential effects on tubulin activity (Läppchen et al 2008).…”

“…Many other compounds that interfere with FtsZ polymerization have also been identified, which bind to FtsZ at different sites other than the nucleotide-binding sites (Kapoor & Panda 2009, Panda et al 2016. It is highly useful in terms of specificity, to identify anti-FtsZ agents that target unique sites in the protein, and not the nucleotide-binding site, which is similar to that in mammalian tubulin.…”

Design and synthesis of (Z/E)-2-phenyl/H-3-styryl-2H-chromene derivatives as antimicrotubule agents

“…14 Various hybrid combretastatin analogs have been designed and synthesized; among them, cis restricted heterocycles, fused heterocycles and nonsubstituted aromatic ring analogs of CA4 are most important. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Not only cis stilbene but also trans-stilbene based natural product and synthetic analogs show pronounced anticancer and antiapoptotic activities; among them, resveratrol and its analogs are most important. 14,34 Nowadays, the preparation of hybrid compounds that possess important skeletons present in drugs/clinical agents has become an important research area for medicinal chemists.…”