Abstract
Furocoumarins are natural photosensitizing drugs used in PUVA photochemotherapy and in photopheresis. Their therapeutic effectiveness is connected to the lesions they induce to various cell components, membranes, ribosomes, mitochondria, and in particular to DNA, damaged by formation of monofunctional adducts and of inter‐strand cross‐links (ISC). ISC represent a severe damage, mainly correlated to the main side effects observed in photochemotherapy, skin phototoxicity and genotoxicity. Searching for new monofunctional derivatives, two tetramethylfuroquinolinones, 1,4,6,8‐tetramethyl‐2H‐furo[2,3‐h]quinolin‐2‐ one (FQ) and 4,6,8,9‐tetramethyl‐2H‐furo[2,3‐h]‐quinolin‐2‐one (HFQ) were studied. Both compounds are very active; however while FQ produced many chromosomal aberrations and strong skin erythemas, HFQ practically did not induce such side effects. FQ and HFQ formed high levels of monoadducts but no ISC in DNA, but both provoked many DNA‐protein cross‐links (DPC). FQ induced these lesions by a biphotonic reaction: at first a furan‐side monoadduct is formed, which is then converted into a DPC; thus the FQ molecule seemed to form the bridge between DNA and proteins. HFQ formed DPC by a single step (DPC at zero length, like UVC). For these features, HFQ appears to be the first molecule belonging to a new class of active but not phototoxic drugs for photomedicine.
Highlights
Furocoumarins are active photosensitizing drugs widely used in photomedicine [1], in research on the structure of various biological macromolecules [2] and on DNA repair [3]
FQ and HFQ induce the same kinds of damages into DNA, roughly to the same order of magnitude; in comparison with 8-MOP both compounds are much more effective
This behaviour is consistent with the very high antiproliferative activity tested on the clonal growth of CHO cells; in this test, 8-MOP, despite its capacity of forming inter-strand cross-links (ISC), appeared to be poorly active, even if assayed in more severe conditions
Summary
Furocoumarins are active photosensitizing drugs widely used in photomedicine [1], in research on the structure of various biological macromolecules [2] and on DNA repair [3]. From centuries: ancient Egyptian and Indian physicians used extracts of leaves, seeds or roots from plants containing furocoumarins for the cure of vitiligo since thousands years BC [4] These preparations were applied on the skin or ingested and the patient was exposed to sunlight. Furan side monoadducts can absorb the UVA light and react further with a second pyridine bases, forming a covalent bridge between the two DNA strands (inter-strand cross-links, ISC) [13]. The formation of such bifunctional adducts represents a severe damage, which is regarded as mainly responsible for the side effects of PUVA therapy, the induction of skin erythemas [1] and for genotoxicity [14].
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