P. Rodighiero

4,5‘‐DIMETHYLANGELICIN: A NEW DNA‐PHOTOBINDING MONOFUNCTIONAL AGENT*

Abstract— 4,5′‐Dimethylangelicin is a new angular furocoumarin showing interesting photochemical and photosensitizing properties. In the dark it forms a complex with native DNA having higher values of the binding parameters than angelicin; by irradiation at 365 nm it is able to photobind with DNA several times faster than angelicin and in about the same degree as psoralen, without forming crosslinkages. It therefore behaves as a pure monofunctional reagent. The same high photobinding capacity with DNA is shown also in vivo in Ehrlich ascites tumor cells and bacterial E. coli cells.

6-Methylangelicins: new monofunctional photochemotherapeutic agents for psoriasis

The monofunctional furocoumarins, the 6‐methylangelicins, were tested for their antiproliferative activity with various animal models and for genotoxicity in micro‐organisms and in mammalian cells. The most active compound was 6,4,4′‐trimethylangelicin, which showed a high antiproliferative effect and reduced genotoxicity in comparison with 8‐methoxypsoralen (8‐MOP). Some of these compounds were also tested clinically by topical application on 17 patients with psoriasis. They appeared to be more active than 8‐MOP in clearing psoriasis without inducing skin phototoxicity. The methylangelicins also caused skin pigmentation.

Benzofurocoumarins: new monofunctional DNA-photobinding agents

Abstract— The tetracyclic furocoumarin 2H‐benzofuro[3,2‐g]‐1‐benzo‐pyran‐2‐one and its 4 and/or II methyl analogues have been investigated in their DN A‐photobinding properties. Spectrophotometric and radioactivity measurements show that these compounds exhibit prominent ability to bind to the polynucleotide double helix by covalent photoaddition of the furocoumarin 3,4 double bond.

3,4 AND 4′,5′‐PHOTOCYCLOADDUCTS BETWEEN 4′‐METHYLANGELICIN AND THYMINE FROM DNA

Abstract— Two C4‐cycloadducts between 4′‐methylangelicin and thymine were isolated from the photo‐reaction (365 nm) between this furocoumarin and DNA. Their capacity to undergo photoreversion at 254 nm and their spectroscopic and NMR data allowed us to assign furan‐ and pyrone‐side structures, respectively, to these photocompounds. The former adduct has a cis‐syn configuration; the latter. which was also isolated from a photoreaction between the furocoumarin and thymine in water‐methanol solution, was assigned a cis‐anti structure.

Coumarins from unripe fruits of Poncirus trifoliata

Abstract Petrol extracts of unripe fruits of Poncirus trifoliata L. were found to contain 7-geranyloxycoumarin, bergapten, imperatorin, 6-methoxy-7-geranyloxycoumarin and two new coumarins which were shown by chemical and spectroscopic means to be 7-(3′-methyl-2′,3′-epoxybutyloxy)-8-(3″-methyl-2″,3″-epoxybutyl)coumarin and 7-(3′-methyl-2′,3′-epoxybutyloxy)-8-(3″-methyl-2″-oxobutyl)coumarin respectively.

5-Methylangelicin: a new highly photosensitizing angular furocoumarin.

5-Methylangelicin, a new highly photosensitizing angular furocoumarin, was studied in 2 different biological systems, the T2 phage and Ehrlich ascites tumor cells; in comparison with angelicin, the parent compound, it was several times more active.

PHOTOPHYSICAL BEHAVIOR OF ANGELICINS AND THIOANGELICINS : SEMIEMPIRICAL CALCULATIONS AND EXPERIMENTAL STUDY

The decay processes of the lowest excited singlet and triplet states of five methylated angelicins (4,6,4′‐trimethyl‐angelicin, MA, and four methylated thioangelicins, MTA; see Scheme 1) were investigated in live solvents by stationary and pulsed fluorometric and flash photolytic techniques. In particular, the solvent effects on absorption, fluorescence, quantum yields of fluorescence (φF) and triplet formation (φT), lifetimes of fluorescence (τF) and the triplet state (τT) and the quantum yields of singlet oxygen production (φΔ) were investigated. Semiempirical (ZINDO/S‐CI) calculations were carried out to obtain information (transition probabilities and nature) on the lowest excited singlet and triplet states. The quantum mechanical calculations and the solvent effect on the photophysical properties showed that the lowest excited singlet state (S1) is a partially allowed π,π* state, while the close‐lying S2 state is n,π* in nature. The efficiencies of fluorescence, S1→T1 intersystem crossing (ISC) and S1→ S0 internal conversion (IC) strongly depend on the energy gap between S1, and S2 and are explained in terms of the so‐called proximity effect. In fact, for MA in cyclohexane, only the S1→ S0 internal conversion is operative, while in acetonitrile and ethanol, where the n.π* state is shifted to higher energy, the efficiencies of fluorescence and ISC increase significantly. The energy gap between S1 and S2 increases in MTA, where the furanic oxygen is replaced by a sulfur atom. Consequently, the solvent effect on the photophysical parameters of MTA is less marked than for MA; e.g. fluorescence and triplet‐triplet absorption are also detectable in the nonpolar cyclohexane. The lowest excited singlet state of molecular oxygen O2(1Dg) was produced efficiently in polar solvents by energy transfer from the T1 state of MA and MTA.

Synthesis and biological activity of linear and angular 4-methoxymethylthienocoumarins and 4-acetoxymethylthienocoumarins

This paper reports the synthesis of 4-methoxymethyl and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one as well as 4-methoxymethyl- and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[2,3-h]-1- benzopyran-2-one. The synthesized derivatives were tested on human cells in UVA irradiation conditions. Skin phototoxicity and cross-link formation in DNA were also studied. Results indicate that the new thienocoumarins have good antiproliferative activity, greater than that of the well-known photochemotherapeutic drug 8-methoxypsoralen, but they are practically devoid of skin photosensitization effects.

Pyranocoumarins as potential photochemotherapeutic agents: theoretical and physico-chemical studies on the mechanism of action

Abstract The interactions between 2 angular pyranocoumarins and DNA have been studied in both ground and excited states. The compounds are able to intercalate inside DNA in a non-covalent manner and, under UV-A irradiation, to photobind covalently, forming pyran-side monoadducts and cross-links. The crystal structure of 4,6-dimethylpyranocoumarin was determined by X-ray diffraction techniques, and molecular arrangements in both ground and excited (singlet and triplet) states were calculated by the MNDO method. Results are discussed in terms of intercalation in the ground state, as shown by linear dichroism measurements, and covalent photobinding to pyrimidine bases of DNA under UV-A excitation.

4′,5′-SUBSTITUTED METHYLANGELICINS: PHOTOCYCLOADDUCTS WITH PYRIMIDINE BASES OF DNA

The isolation and characterization of photocycloadducts with pyrimidine bases from DNA samples irradiated (365 nm) in the presence of four 4′,5′‐substituted methylangelicins was performed. All these furocoumarins yielded mainly the cis‐syn furan‐side cycloadduct with thymine. For 4′,5′‐dimethyl‐, 5,4′,5′‐trimethyl‐ and 6,4′,5′‐trimethylangelicin this adduct was accompanied by two pyrone‐side adducts (cis‐syn and cis‐anti), whereas the 4,4′,5′‐trimethyl derivative gave the furan‐side adduct with cytosine.