Inhibition of microtubule function using
tubulin targeting agents has received growing attention in the last several decades. The
indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as
antimitotic agents.
Indole-based
chalcones, in which one of the aryl rings was replaced by an
indole, have been explored in the last few years for their anticancer potential in different
cancer cell lines. Eighteen novel (3',4',5'-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human
cancer cell lines. The highest IC50 values were obtained against the human promyelocytic
leukemia HL-60 cell line. This series of
chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl
indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3',4',5'-trimethoxyphenyl)-2-propen-1-one framework. The structure-activity relationship (SAR) of the
indole-based
chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (
hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the
indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted
indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a
hydrogen on the
indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the
indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7
cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ∼1 μM) in the human
myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of
tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the
indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3',4',5'-trimethoxyphenyl scaffold.