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, 9 (3), e85380

Docking, Synthesis and Antiproliferative Activity of N-acylhydrazone Derivatives Designed as Combretastatin A4 Analogues


Docking, Synthesis and Antiproliferative Activity of N-acylhydrazone Derivatives Designed as Combretastatin A4 Analogues

Daniel Nascimento do Amaral et al. PLoS One.


Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a-r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. Anti-microtubule agents: vincristine (1), vinblastine (2), paclitaxel (3), CA-4(4) and its chalcone analogue (6).
Figure 2
Figure 2. Initial conception and molecular design of N-acylhydrazone derivatives 5a–s.
Figure 3
Figure 3. Polar interactions between CA-4 (A) or LASSBio-1593 (B) with the colchicine binding site of β-tubulin (PDB code: 1sa0).
Figure 4
Figure 4. Conditions and reagents: a) 80% aq. N2H4.H2O, EtOH, reflux, 2 h, 93%.
b) ArCHO, EtOH, HCl (cat), r.t., 0.5–4 h, 62–95%.
Figure 5
Figure 5. ORTEP view of compound 5b with the atom displacement ellipsoids drawn at a 50% probability level.
Figure 6
Figure 6. Design of compounds 9–12 from molecular modification of prototype 5b.
Figure 7
Figure 7. Conditions and reagents: a) Phenyl chloroformate, CHCl3, reflux, 2 h, 47%; b) N2H4.H2O, toluene, r.t., 72 h, 64%; c) PhCHO, EtOH, HCl (cat), r.t., 1 h, 83%.
Figure 8
Figure 8. Best poses of compounds 5b (A), 10 (B), 9 (C) and 12 (D) at the colchicine binding pocket β-tubulin (PDB code: 1sa0).

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This work was supported by CNPq (BR), FAPERJ (BR) and INCT-INOFAR (BR, 573.564/2008-6 and E-26/170.020/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.