Synthesis of heterocycle-based analogs of resveratrol and their antitumor and vasorelaxing properties.
New resveratrol (RES) analogs were developed by replacing the aromatic 'core' of our initial naphthalene-based RES analogs with pseudo-heterocyclic (salicylaldoxime) or heterocyclic (benzofuran, quinoline, and benzothiazole) scaffolds. The resulting analogs were tested for their antiproliferative and vasorelaxing effect, two typical properties shown by RES. Some of the new compounds confirmed strong antiproliferative activities, comparable to that previously found with the most active naphthalene-based analog. In particular, 3-(3,5-dihydroxyphenyl)-7-hydroxyquinoline exhibited the most potent antiproliferative effect (IC50=17.4 microM). In vascular assays, the highest levels of potency (pIC50=4.92) and efficacy (Emax=88.2%) were obtained with 2-(3,5-dihydroxyphenyl)-6-hydroxybenzothiazole. A conformational analysis of these compounds indicated that the antiproliferative activity on MDA-MB-231 cancer cells can be correlated to a common sterical profile of the most active compounds and, in particular, to the spatial arrangement of the three phenolic groups. Furthermore, the vasorelaxing properties showed a good correlation with the electronic properties measured through the electrostatic molecular potential (ESP).
Bertini
Simone
S
Department of Pharmaceutical Sciences, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Calderone
Vincenzo
V
Carboni
Isabella
I
Maffei
Roberta
R
Martelli
Alma
A
Martinelli
Adriano
A
Minutolo
Filippo
F
Rajabi
Mehdi
M
Testai
Lara
L
Tuccinardi
Tiziano
T
Ghidoni
Riccardo
R
Macchia
Marco
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D000077185:Resveratrol; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D013267:Stilbenes; D014665:Vasodilator Agents; D000077185:Resveratrol