Angular furoquinolinones, psoralen analogs: novel antiproliferative agents for skin diseases. Synthesis, biological activity, mechanism of action, and computer-aided studies.
With the aim of obtaining new potential photochemotherapeutic agents, having increased antiproliferative activity and decreased undesired effects, we have prepared some new furoquinolinones. Two of them have been studied in detail: 1,4,6,8-tetramethyl-2H-furo[2,3-h]-quinolin-2-one (8), and 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one (10). These compounds form a molecular complex with DNA, undergoing intercalation inside the duplex macromolecule, as shown by linear flow dichroism. The complexed ligands, by subsequent irradiation with UV-A light, photobind with the macromolecule forming only monocycloadducts with thymine with cis-syn configuration. In order to evaluate the electronic effects induced by the nitrogen atom in position 1 of 8, semiempirical calculations have been performed on both 4,6,4'-trimethylangelicin (TMA) and 8. The results obtained do not clearly differentiate between the two molecules which, at this level of approximation, show the possibility of photoreaction with both the 3,4- and 8,9-olefinic bonds for 8 and the 3,4- and 4',5'-bonds for TMA. In the lower energy conformation of intercalated 8, the furan ring is turned toward the minor groove of the polynucleotide, in such a way that photoreaction of this ring with thymine is favored. These compounds unexpectedly inhibit DNA and RNA synthesis in Ehrlich cells, in the dark. They also show a strong photoantiproliferative activity, 2 orders of magnitude higher than 8-methoxypsoralen (8-MOP), the most used drug for photochemotherapy. Their mutagenic activity on Escherichia coli is similar to that of TMA and 8-MOP. On the basis of these results, the compounds should deserve evaluation of their activity in the treatment of hyperproliferative skin diseases.
Rodighiero
P
P
Centro di Studio sulla Chimica del Farmaco e dei Composti Biologicamente Attivi del CNR, Padova, Italy.
Guiotto
A
A
Chilin
A
A
Bordin
F
F
Baccichetti
F
F
Carlassare
F
F
Vedaldi
D
D
Caffieri
S
S
Pozzan
A
A
Dall'Acqua
F
F
D004247:DNA / Q000378:metabolism; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity; D017900:Myoviridae / Q000187:drug effects; D010778:Photochemotherapy; D012313:RNA / Q000096:biosynthesis; D012871:Skin Diseases / Q000188:drug therapy*
D011564:Furocoumarins; D009153:Mutagens; D012313:RNA; D004247:DNA; C041621:4,4',6-trimethylangelicin