Z. Photochem. Photobiol. B: Biol., 24 (1994) 129-139 129 Biophysical and biological properties of newly synthesized dio&&oumarin derivatives II. Dark and photoinduced cells effects on T7 phage, yeast arid HeLa Gabriella Csik and Gyiirgyi Ront6 Institute of Biophysics, Semmelweis University of Medicine, Puskin u. 9, H-1088 Budapest (Hungary) Silvano Nocentini, Simone Averbeck and Dietrich Averbeck URA 1292 du CNRS, Institut Curie - Section de Biologie, 26 rue d’Ulm, F-75231 Paris Ceder 05 (France) Thierry Besson Laboratoire de Genie Proteique - Physicochimie des Substances Naturelles, Universite’ de la Rochelle, 23 rue Albert Einstein, F-17071 La Rochelle Ceder 9 (France) Gerard Coudert and G&ald Guillaumet Laboratoire de Chimie Bio-Otganique et Analytique assock! au CNRS, Universite d’Orleans, BP 6759, F-45067 Orleans Cedex 2 (France) (Received January 3, 1994; accepted April 7, 1993) zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Abstract The dioxinocoumarin derivatives 5H-[2]benzopyrano-[3,4-g][1,4]benzodioxin-S-one (I), SH-[Zlbenzopyrano-[3,4- g][2,3]-dihydro-[1,4]benzodioxin-5-one (II), 6H-[2]benzopyrano[3,4-fj-1,4-benzodioxin-6-one (III) and 6H- [2]benzopyrano[3,4-fl-2,3-dihydro-l,4-benzodioxin-6-one (IV) were synthesized. Their biological effect was studied in the presence and absence of UVA radiation, and compared with that of 8-methoxypsoralen (8-MOP) and angelicin derivatives on T7 phage, diploid yeast (Saccharomyces cerevisiae) and HeLa cells. The photobiological activities of compounds I and III were stronger than that of 8-MOP in phage inactivation and DNA synthesis inhibition in HeLa cells, whereas compounds II and IV, with a saturated dioxin ring, showed very poor activity. The photosensitizing activity of dioxinocoumarins on phage inactivation decreased by a factor of two to three in the absence of oxygen. Treatments with compound I and UVA in the presence of oxygen modified the helical structure and stability of phage DNA and proteins. Compounds I and II were more active than IV for photoinduced cell killing in yeast, although always less active than 8-MOP. At comparable photocytotoxic levels, compounds I and III were as strong inducers of cytoplasmic “petite” monofunctional mode of action with cellular DNA. mutants in yeast as angelicin, suggesting a possible Key words: Dioxinocoumarins; Dark effect; Photosensitization; T7 phage; Yeast; Cytoplasmic “petite” mutants; DNA synthesis inhibition; HeLa cell 1. Introduction zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Various furocoumarins (FCs) are used in the treatment of hyperproliferative skin diseases and in cosmetics [l]. The molecular basis of the pho- tobiological activity of FCs involves oxygen-de- pendent and oxygen-independent reactions. Pho- tobinding of the drug to DNA is held at least partly responsible for the antiproliferative effect of FCs in psoralen plus UVA (PUVA) therapy of psoriasis. Comparative studies on the possible therapeutic potency of different derivatives have usually focused on their photobinding to DNA. Since cross-links are thought to be responsible for most side effects, FCs capable of producing only monoadducts with DNA have been prepared and studied. This can be accomplished in two ways: (i) by using compounds with an angular structure, which cannot form cross-links for geometrical rea- sons [2, 31; (ii) by blocking one of the reactive loll-1344/94/$07.00 0 1994 Elsevier Science S.A. All rights reserved SSDZ 1011-1344(94)07015-G