Sebastiano Marciani Magno

Photochemotherapy in the Treatment of Cancer

The development of therapies which are selective for tumor tissues is one of the most important goals in anticancer research. Within this framework photochemotherapy can be considered a very promising approach. Its therapeutic effectiveness depends on two connected factors: drug and light. The drug (photosensitizer) is able to exert an antiproliferative effect only after interaction with suitable light. Both the photosensitizing drug and light alone are ineffective at doses used for these treatments. Nowadays, photochemotherapy is used in the treatment of cutaneous T-cell lymphoma and cavitary tumors. In the first case the photosensitizer is a psoralen derivative (P) and long-wavelength ultraviolet radiation (UVA) is used (PUVA therapy). In the second case, the treatment with porphyrins, porphyrin-based and non porphyrin-based photosensitizers is followed by irradiation with 600-1000 nm light (photodynamic therapy, PDT). This review is concerned with PUVA and PDT treatments of cancer. The molecular mechanisms considered accountable for the photochemotherapeutic effects are discussed, the development of new chemical structures aimed at improving the effectiveness and/or overcoming some undesired side effects will also be reported. Moreover, some clinical applications will be described.

Synthesis, in vitro antiproliferative activity and DNA-interaction of benzimidazoquinazoline derivatives as potential anti-tumor agents

The synthesis of benzimidazoquinazoline derivatives bearing different alkylamino side chains is reported. All new compounds tested by means of an in vitro assay exhibit antiproliferative activity toward human tumor cell lines. The cytotoxic effect depends on the type of side chain inserted in the planar nucleus and in some cases it is comparable to that of the well-known drug ellipticine. In order to understand the mechanism of action of these compounds, the interaction with DNA has been investigated. Linear flow dichroism measurements allowed us to verify the formation of a molecular complex with DNA and the corresponding geometry of interaction. Intrinsic binding constants have also been evaluated by performing fluorimetric titrations.

Synthesis, DNA binding and in vitro antiproliferative activity of purinoquinazoline, pyridopyrimidopurine and pyridopyrimidobenzimidazole derivatives as potential antitumor agents

Abstract In the search for new antitumor agents, 8,10-dimethylpurino[7,8-a]quinazoline-5,9, 11(6H,8H,10H)-triones 1 , 8,10-dimethylpyrido [2′,3′:4,5]pyrimido[1,2-f]purine-5,9,11 (6H,8H, 10H)-triones 2 , and 5,7-dihydro-5-oxopyrido[3′,2′:5,6]pyrimido[1,2-a]benzimidazoles 3 , a series of new planar heteropolycyclic compounds, were synthesized. The approach to understanding their structure-activity relationship involved a physico-chemical investigation of the binding process of these molecules to DNA, considered to be an important target for drug action, and an examination of their biological activity. Thermodynamic parameters of the DNA binding process, intrinsic binding constant and exclusion parameter were determined. The mode of interaction was additionally investigated by means of linear flow dichroism studies. Evaluation of the biological activity included cell growth inhibition in human tumoral cell lines and the ability to induce DNA cleavage in the presence of eukaryotic topoisomerase II. Only compounds of the purinoquinazoline series 1 , which are able to form a complex with DNA and to inhibit the topoisomerase II, show antiproliferative activity.

Dialkylaminoalkylindolonaphthyridines as potential antitumour agents: Synthesis, cytotoxicity and DNA binding properties

The synthesis of new planar derivatives characterised by the presence of an indolonaphthyridine nucleus, carrying a dimethylaminoethyl or a dimethylaminopropyl side chain is reported. The antiproliferative activity of the new products was tested by means of an in vitro assay on human tumour cell lines (HL-60 and HeLa). A number of compounds (1a-d, 1h) showed IC(50) values comparable to that obtained with the well-known drug ellipticine on the HL-60 cell line. The interaction with DNA was also investigated. Linear flow dichroism measurements allowed us to understand the interaction geometry. The thermodynamic parameters of the binding process, i.e. intrinsic binding constant and exclusion parameter, were determined by fluorimetric titration.

Interaction of deoxyribonucleic acid with anthracenedione derivatives

Abstract Spectrophotometric, calorimetric and chrioptical techniques have been used to investigate the interaction of two new anthracenedione derivatives, 1-(ω-diethylaminopropylamido)-4-hydroxy-9,10-anthracenedione hydrochloride (I) and 1-(ω)-diethylaminopropylamido)-2-methoxy-4-hydroxy-9,10-anthracenedione hydrochloride (II) to DNA. Measurements were carried out at four different Na + concenetrations. From the dependence of the binding constant on ionic strength the number of ion pairs formed between the ligand and DNA, along with the binding free energy were estimated. Calorimetric measurements show that the binding process is exothermic for both ligands. Experiments carried out with DNA from various sources indicate no marked preference for G-C or A-T binding sites. Compounds I and II increase the T m for DNA melting by more than 25°C at high drug/base pair ratios. Circular dichroism studies indicate that the structural properties of DNA are substantially affected by the interaction with the above mentioned compounds. All data from these studies are consistent with an intercalative mechanism of binding for the anthracendione derivatives to DNA.

A new psoralen derivative with enlarged antiproliferative properties.

Following our results with benzopsoralens as potent photochemotherapeutic agents, we report the antiproliferative evaluation of nitrogenated isoster upon and without UVA irradiation. The evaluated pyridazinopsoralen showed a higher photochemotherapeutic activity with respect to the well-known drug, 8-MOP, and a significant cytotoxicity, also in the dark. This result enlarges the interest in this tetracyclic psoralen derivative skeleton in the search of new anticancer agents.

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.

Thienocoumarin derivatives: interaction with nucleic acids and synthetic polydeoxyribonucleotides.

This paper reports the photobiological properties of two new thienocoumarins, 4,6,9-trimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound I) and the 6,9-dimethyl-4-methoxymethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound II). Cell growth inhibition studies have revealed significant antiproliferative potency on human tumor cell lines. The photoaddition process of these tritium-labeled derivatives was investigated using various nucleic acid structures (calf thymus DNA, bacterial DNA, and synthetic polydeoxyribonucleotides). The results obtained show that both compounds photobind to DNA to a higher extent than 8-MOP, taken as the reference drug. The capacity to form interstrand crosslinks into DNA helix was also evaluated. Interestingly, notwithstanding the lack of cutaneous phototoxicity, II revealed a good ability to induce diadduct formation.

Pyridazinopsoralens of wide chemotherapeutic interest

The synthesis of new 6,10-dimethylpyridazino[4,5-h]psoralens, carrying no (4), one (5), or two (6-9) dialkylaminoalkylcarboxamide side chains on the pyridazine ring is reported. All compounds exert a significant photoantiproliferative activity. Moreover, the derivatives characterised by the protonable side chains show a notable cytotoxicity in the dark. The investigation on the mechanism of action demonstrated the capacity to intercalate into DNA base pairs and to inhibit the relaxation activity of topoisomerase II.

Thermodynamics and Stereochemistry of the Interaction between Anthraquinone Drugs and DNA

The majority of the drugs used today in cancer chemotherapy act as nucleic-acid synthesis inhibitors. The inhibitory process may occur either through direct interaction with the nucleic-acid, giving a stable complex, or through interference with enzymes acting at the nucleic acid replication or transcription level (1,2). The anthracycline antibiotics Daunomycin and Adriamycin are among the most important derivatives for which the mechanism of action is believed to consist of a binding process to DNA. These compounds possess a tetrahydrotetracenedione chromophore, containing three coplanar hexa-atomic rings. Numerous investigations have demonstrated the formation of an intercalation complex with DNA (2–5). At the molecular level, the aromatic ring system of the anthracycline slips into adjacent base pairs of the polynucleotide, whereas the cyclohexene moiety, connected to the amino-sugar is located in the minor groove of the double-helix (6,7). The complex is further stabilized by electrostatic interactions between the positively charged protonated amino group of the polymer chain.