Antiproliferative Activity and Phototoxicity of some Methyl Derivatives of 5–Methoxypsoralen and 5–Methoxyangelicin

Abstract

Ihstrcrcr:The in vitro antiproliferative activity and in i t v o phototoxicity of some methyl derivatives of ~-methoxypsoraleit ,~n d 5-methoxyangelicin, i.e. 4,4'-dimethyl-5-methoxyangelicin (compound I), 3,4'-dimethyl-5-methoxyangelicin (compound 11). 4,4'-dimethyl-5-methoxypsoralen (compound 111); and 3.4'-dirnethyl-S-methoxypsoralen (compound lV), have been investigated. The effects of the compounds were evaluated in vi/ru on HL60 and A43 I cells, using 5-niethoxypsoralen ; I S the reference compound. In both cell lines compound 1, 11 and 111 showed better antiproliferative activity than coinpound 1V and 5-methoxypsordlen. Scanning electron microscopy revealed [hat all the compounds induced the formation of blebs and blisters on a A431 cell surface. Significant variations in the nuclear area strictly related to the toxicity of the compounds have been shown in both cell lines. Skin Irritancy in viiw was evaluated by mean of histopathological responses on guinea-pig skin. For each compound a damage index was determined by morphometrical analysis of empty spaces in the epidermis. Histopathology revealed skin phototoxicity of compounds which lacked erythemogenic activity by visual ,coring. By coupling cytotoxicity data in virro to skin sensitization ones in viva. compound I proved a promising candidate for use in clinical trials since due to a high inhibitory effect on the growth of human cell lines coupled to low skin phototoxicity.

Trimethylangelicin reduces IL-8 transcription and potentiates CFTR function

“…Interestingly, in the case of linear furocoumarins, the PSR monoadducts formed in the DNA can further react photochemically with a pyrimidine base on the complementary strand of the DNA, thus leading to interstrand cross-links (ICL). On the other hand, and relevant to biomedical applications, angular PSRs, such as TMA, allow only monofunctional DNA binding upon irradiation with UV light, thus reducing undesirable side effects, especially longterm ones, such as genotoxicity and risk of skin cancer (6,7,13,23,30). It is well known indeed that PSRs cause cell damage by covalent binding to DNA following UVA irradiation, and these molecules exhibit a planar tricyclic structure with two photoreactive sites (3,4-pyrone and 4=,5=-furan double bonds).…”

“…Psoralens (PSRs) are well-known furocoumarins belonging to the class of photosensitizers used for their activity in the treatment of various chronic inflammatory skin diseases (6,7,12,13,23,30,37), and they are characterized by a differently substituted tricyclic aromatic skeleton, derived from condensation of a coumarin nucleus with a furan ring. Among PSR-related compounds, the angular angelicin (ANG)-like isomers are both synthetic and natural compounds, e.g., derived from the medicinal plant Angelica arcangelica, that could exhibit interesting pharmacological activity compared with linear PSRs, showing low toxicity and low DNA-binding activity (6,23).…”

Behavioral and biochemical studies of total furocoumarins from seeds of Psoralea corylifolia in the forced swimming test in mice

“…Furocoumarins are the most widespread secondary metabolites in this species (Wang et al, 1999). They possess anti-inflammatory, immunomodulatory and antiproliferative activities (Kozenitzky et al, 1992;Neuner et al, 1994;Conconi et al, 1998). Administration of furocoumarin psoralen inhibited hepatic melatonin metabolism to treat seasonal affective disorders in humans in Finland (Partonen, 1998).…”

Increase in γ-globin mRNA content in human erythroid cells treated with angelicin analogs

“…Interestingly, in the case of linear furocoumarins (such as 5-MOP and 8-MOP) the psoralen monoadducts formed in the DNA can further react photochemically with a pyrimidine base on the complementary strand of the DNA, thus, leading to ICL. On the other hand, and relevant to biomedical applications, angular psoralens such as ANG and TMA allow only monofunctional DNA binding, thus, reducing undesirable side effects, especially long-term ones, such as genotoxicity and risk of skin cancer [13][14][15][16][17][18]. However, interactions with other molecules relevant for activation of the erythroid program cannot be excluded.…”

“…Among molecules able to interact with DNA, we have recently analyzed angelicin (ANG) [12], a well-known furocoumarin belonging to the class of photosensitizers used for their antiproliferative activity in the treatment of various skin diseases [12][13][14][15][16][17][18][19][20]. ANG derivatives are both natural or synthetic compounds present for instance in Angelica archangelica medicinal plant that could exhibit interesting pharmacological activity when compared with the linear psoralens, including low toxicity and different DNA-binding modality.…”