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Benzo[a]carbazole compounds and uses

Anti-infectivesAntitumoralsImmunologyMDM2-p53Multitherapy.

Introduction

The invention relates to compounds of formula I where a proper combination of substituents produces a modulation of apoptosis by inhibition of complex MDM2-p53. The inhibition of MDM2-p53 interaction is a therapeutic target in cancer, immunological and infectious diseases where a degradation of p53 can induce a pro-carcinogenic effect in host cells. RM37 is an example of compounds of formula I.

Technical features

The invention relates to compounds of formula I where a proper combination of substituents can confer a modulatory activity on apoptosis by inhibition of the binding between MDM2 (or MDMX) and the transcription factor p53. Degradation of p53 can induce a pro- carcinogenic effect in host cells. The inhibition of MDM2-p53 interaction is a therapeutic target in cancer, immunological and infectious diseases (bacterial, viral or protozoal) Molecules I properly substituted can be used for therapeutic purposes but can be also functionalized to become diagnostic probes. RM37 is a representative example of molecules I, able to effectively bind the intracellular target MDM2 without having antibiotic activity and is characterized by a low toxicity for host cells.

Possible Applications

I as Chemotherapeutics or use of labelled derivatives of I as diagnostic probes in pathologies with loss of p53 activity or MDM2/X overexpression in:

  • Oncology;
  • Immunology;
  • Infectious diseases (bacterial, viral or protozoal);
  • Haematology;
  • Gastroenterology;
  • Neurology;
  • Cardiopulmonary diseases.

Advantages

  • Potency and selectivity for the target (RM37 IC50 = 220 nM, Nutlin-3 IC50 = 290 nM);
  • Low toxicity for host cells;
  • Lack of antibiotic activity;
  • Good bioavailability;
  • Feasible synthetic process.