Diseño, síntesis y actividad biológica de nuevas benzoxatiepinas, compuestos relacionados y conjugado ácido hialurónico-pentamidina

Resumen

Summary Breast cancer still remains as the second most common cancer worldwide. Although chemotherapy and radiotherapy can effectively reduce tumour mass and provide temporary remission, relapse occurs in many cases. This is due to an intrinsically chemotherapy-resistant subpopulation of cells with a strong ability to self-renew, known as cancer stem cells (CSC). This subset of cells may also contribute to tumour initiation, progression and metastasis. Thus, drugs that target CSC offer great promise for cancer treatment, particularly in combination with chemotherapy. Leishmaniasis is a vector-borne tropical disease caused by different species of obligate intra-macrophage protozoa of the genus Leishmania transmitted to mammalian hosts during a blood meal of infected female phlebotomine sandflies. This neglected disease is endemic in 88 countries and affects approximately 12 million people worldwide, with 350 million people considered at risk. The most severe form of the disease (i.e. visceral) can claim victims if left untreated and the few accessible drugs have several drawbacks including major side effects and parenteral administration. In this context, the investigation of new delivery modalities which might reduce the toxicity and increase the bioavailability of the drugs currently in the market represents a valid strategy to counter these problems. In relation to our anticancer programme, two distinct series of the 3-amino-1,5-benzoxathiepin scaffold, derived from L-cysteine, were synthesized and evaluated for their potency towards anti-proliferative activity in the breast cancer MDA-MB-231 and MCF-7 cells, and in the ovarian carcinoma SKOV-3 cell line. (3R)-Amino-3,4-dihydro-2H-1,5-benzoxathiepin was diversified in two forms: a) By incorporating different amino acids at its position 3, through an amide bond, making up the chemical library 1, b) and b): by construction of the purine ring to give 6-chloro-9-[2-(3,4-dihydro-2H-1,5-benzoxathiepin-(3R)-yl]-9H-purine [(R)-47]. Nevertheless, when the introduction of iodine is tried at position 2 of the purine ring of (R)-47 by the three successive processes including the regiospecific lithiation/quenching with an excess of the Harpoon´s base (lithium 2,2,6,6-tetramethylpiperidine) and tributyltin/iodination, 2-{[2-(6-chloro-2-iodo-9H-purin-9-yl)prop-2-en-1-yl]thio}phenol (56) was obtained as a result of the breaking the O-CH2 bond of the seven-membered ring of the non-obtained 6-chloro-9-[2-(3,4-dihydro-2H-1,5-benzoxathiepin-(3R)-yl]-2-iodo-9H-purine. Compound 56 shows activity against cancer cells and an inhibitory effect over kinases involved in cell survival, proliferation and carcinogenesis. Interestingly, 56 shows anti-migratory activity and inhibits mammosphere formation at the micromolar range, demonstrating activity against cancer stem cells. Although further studies of its targets and mechanism of action are needed, these findings support the therapeutic potential of this compound in cancer. In relation to leishmania, herein we present the development of a macrophage mediated drug targeting delivey system by conjugating the anti-leishmanial drug pentamidine (Pent) with the biocompatible polymer hyaluronic acid (HA), the latter employed at the same time as delivery platform and targeting scaffold. Biological assays against Leishmania major amastigote-infected macrophages and primary bone marrow derived macrophages confirmed the validity of our strategy as the resulting bioconjugate HA-Pent increased both the potency and the selectivity index of the drug. Finally, in this doctoral thesis several chemical structures with an expected exalted anti-proliferative activity are proposed. At the same time, the univocal synthesis of 56 is recommended in order to prove unequivocally its scaffold.