P. Rodighiero et al., ANGULAR FUROQUINOLINONES, PSORALEN ANALOGS - NOVEL ANTIPROLIFERATIVE AGENTS FOR SKIN DISEASES - SYNTHESIS, BIOLOGICAL-ACTIVITY, MECHANISM OF ACTION, AND COMPUTER-AIDED STUDIES, Journal of medicinal chemistry, 39(6), 1996, pp. 1293-1302
With the aim of obtaining new potential photochemotherapeutic agents,
having increased antiproliferative activity and decreased undesired ef
fects, ave have prepared some new furoquinolinones. Two of them have b
een studied in detail: 1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-on
e (8), and 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one (10). Thes
e compounds form a molecular complex with DNA, undergoing intercalatio
n inside the duplex macromolecule, as shown by linear flow dichroism.
The complexed ligands, by subsequent irradiation with UV-A light, phot
obind with the macromolecule forming only monocycloadducts with thymin
e with cis-syn. configuration. In order to evaluate the electronic eff
ects induced by the nitrogen atom in position 1 of 8, semiempirical ca
lculations 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 possibil
ity of photoreaction with both the 3,4- and 8,9-olefinic bonds for 8 a
nd 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 wit
h thymine is favored. These compounds unexpectedly inhibit DNA and RNA
synthesis in Ehrlich cells, in the dark. They also show a strong phot
oantiproliferative activity, 2 orders of magnitude higher than 8-metho
xypsoralen (8-MOP), the most used drug for photochemotherapy. Their mu
tagenic activity on Escherichia coli is similar to that of TMA and 8-M
OP. On the basis of these results, the compounds should deserve evalua
tion of their activity in the treatment of hyperproliferative skin dis
eases.