Derivatives of benzoheteroepinic enantiomers used as anticarcinogenic
The present invention bases on the two enantiómeros of the compound (RS)-9-[1-(p-nitrobencénsulfonil)-1,2,3,5-tetrahidro-4,1-benzoxazepin-3-il]-2,6-dicloro-9H-purina (ACG-812bF3), which disable EGFR (recipient of factor of epidermal growth) and VEGF (factor of vascular growth endotelial, induction of the stop of the synthesis of proteins across the fosforilación of the factor of translation IF2-alpha), produce a high level of apoptosis in tumour cells and in addition, demonstrate neither sharp toxicity nor chronicle.
The tests of antitumoral activity have demonstrated that these compounds possess a great antitumoral power with values inside the range nanomolar and selectivity on tumour lines in experiments realized on cellular lines of colon and spring.
As for the analysis of the action on proteins tirosina quinasas, the results indicate that an inhibition of the activity exists of quinasa presents in the membrana celular up to others located in the core. The analysis detailed of these results indicates that the compounds possess a selective activity on EGF-R wt and the recipient HER-2 (ERBB2), which they find sobreexpresados in the tumour cells (especially in cancer of breast), which prevents that they are formed dímeros and that there is induced the waterfall of corresponding signposting, responsible for the cellular
proliferation.
In addition, to the used doses, the compounds demonstrate a powerful inhibition of the activity angiogénica induced by the administration of the VEGF-R. It is prominent that the forms enantiómeras possess a major inhibitory capacity of the tirosina quinasa with regard to the racemic, and enclosed compound they disable of considerable form the activity of quinasas that are not altered by the racemic one. Such it is the case of the complex CDK6/CycD1 that is important for the progression in the phase G1 of the cellular cycle and in the transition G1/S. In addition, this complex regulates the activity of the suppressing gene of tumors Rb. Of the caress way, PKC-alpha acts as tumour promoter, who intervenes in processes of adhesion, transformation and control of the cellular cycle, and that is inhibida significantly for the enantiómeros E1 and E2
Innovations
One of the main advantages of those enantiomers is their specificity over tumor cells, turning out in toxicity trials, both in vitro and in vivo, that is lower, or even null in non-tumor cells. Furthermore, these are powerful tyrosine kynase inhibitors which are overexpressed on the majority of cancers, and also related with proliferation, migration and tumor angiogenesis.
Another main advantages is that these compounds do not induce p53 seryne 16 phosphorilation-dependant apoptosis, and thus, are capable of inducing non-functional apoptosis on cells with non-functional p53, as well as on tumors with a mutated p53 (more of the 50% of malignant tumors).
Fort he last, toxicity tests have been carried out in vivo in Balb/c mice, and in all cases the follow-up of these mice, for a 30-day period after administering these compounds, showed no presence of toxicity signs such as weight loss, hair loss or behavior alterations among others
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