Figure 1.
Anti-microtubule agents: vincristine (1), vinblastine (2), paclitaxel (3), CA-4(4) and its chalcone analogue (6).
Figure 2.
Initial conception and molecular design of N-acylhydrazone derivatives 5a–s.
Figure 3.
Polar interactions between CA-4 (A) or LASSBio-1593 (B) with the colchicine binding site of β-tubulin (PDB code: 1sa0).
Table 1.
Scores estimated by molecular docking (ChemScore fitness function) for colchicine binding site of β-tubulin, cLogP, cLogD7.0, molar refractivity and the aqueous solubility of CA-4 and its N-acylhydrazone analogues 5a–r.
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.
ORTEP view of compound 5b with the atom displacement ellipsoids drawn at a 50% probability level.
Table 2.
In vitro antiproliferative potency (IC50-µM) of compounds 5a–r and the standard CA-4 against tumor cell lines and human lymphocytes.
Table 3.
The selectivity index (SI) of CA-4 and N-acylhydrazones (5a–r).
Figure 6.
Design of compounds 9–12 from molecular modification of prototype 5b.
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.
Best poses of compounds 5b (A), 10 (B), 9 (C) and 12 (D) at the colchicine binding pocket β-tubulin (PDB code: 1sa0).
Table 4.
Antiproliferative activity of compounds CA-4, 5b and 9–12 against HL-60, SF295, HCT-8 and MDA-MB435 tumor cells.
Table 5.
In vivo antiproliferative activity of 5b and 5-fluorouracil (5-FU) in Hollow Fiber Assay (HFA).
Table 6.
Intermolecular hydrogen bond geometry.