1. Insilico design, synthesis and biological evaluation of inhibitors of hypoxia- inducible factor (HIF-1) as antitumor agents Lucía Minini, Maira De Negri, Alicia Merlino, María Laura Lavaggi. LQTC, Medicinal Group, Faculty of Sciences, University of the Republic, Uruguay

2. Hypoxic tumor cell. Human solid tumors are less well-oxygenated than the normal tissues from which they arose. Tumor hypoxia leads to resistance to radiotherapy and anticancer chemotherapy as well as predisposing for increased tumor metastases. Hypoxia induces changes in gene expression profile through the induction of transcription factors called hypoxia -inducible factors (HIF-1) How to treat hypoxic tumor cells?

3. HIF-1  hipoxia Complejo Pol II CBP/p300 HIF-1  HIF-1 Angiogenesis Glucose metabolism Cell growth In normoxic conditions, HIF- 1α is hydroxilated in the ODD and TAD domains, causing degradation and preventing it bind to the transcriptional co-activator p300.

4. Hypoxia inducible factor HIF-1 HIF-1 is a heterodimeric protein that activates transcription of cell survival - related genes. It consists of two subunits, HIF- 1α, regulated by cell oxygenation. Because of this, it is translocated to the nucleus where it dimerizes with HIF- 1β3, and bind to specific DNA sequences known as response elements hypoxia (HRE)

5. McKeown, S.R.; Coweny, R.L.; Williams, K.J. (2007) “Bioreductive drugs: from concept to clinic”. Clinical Oncology, 19, 427-442 Bio-reductive prodrugs.

6. Phenazine 5,10 dioxides derivatives design. Increased toxicity Aromatic amine

7. Phenazine 5,10 dioxides derivatives.

12. HIF-1 Inhibitors: HRE interactive agents

13. 132654 HIF-1 Inhibitors: HRE interactive agents in progress docking studies.

14. 132654

15. Molecular dinamics show intercalation within DNA strands.

16. DNA INTERACTION-Fluorescence spectroscopy Stern-Volmer If 0 / If = 1 + K Q [Q] K Q = (18 ± 1) x 10 -3

17. DNA INTERACTION 1 3 5 6 7 Ksv= (1,0 ± 0,8) x 10 -3 Ksv= (1,5 ± 1,3) x 10 -3 Ksv= (2,7 ± 0,8) x 10 -3.

18. DNA INTERACTION 1 Ksv= (1,0 ± 0,8) x 10 -3 2 Ksv= (7,3 ± 1,7) x 10 -3 8 Ksv= (24,4 ± 2,8) x 10 -3 9 Ksv= (14,3 ± 0,4) x 10 -3

19. DNA INTERACTION 10 Ksv= (10,1 ± 0,4) x 10 -3 11 Ksv= (15,2 ± 0,8) x 10 -3 12 Ksv= (2,8± 0,2) x 10 -3 13 Ksv= (9,3± 0,7) x 10 -3

20. DNA INTERACTION 14 Ksv= (10,7 ± 1,4) x 10 -3 15 Ksv= (8,3 ± 0,4) x 10 -3 16 Ksv= (0,1 ± 0,2) x 10 -3 17 Ksv= (0,1 ± 0,1) x 10 -3

21. Biological evaluation-selective active normoxic compounds

22. Biological evaluation-selective active hypoxic compounds

23. Hystone deacetylase inhibitors In vivo evaluation in progress

25. Hystone deacetylase inhibitors as sensitizers to chemotherapeutic agents.

26. Biological activity-U2O2 osteosarcoma cells.

28. Sensitizer effect in osteosarcoma cells.

29. Perspectives Determine the level of HDAC7 and HIF-1 expression in cells treated with the active compounds under hypoxia, to determine its potential use as a hypoxic tumor cell sensitizer to other chemotherapeutic agents. Determine HIF-1 inhibition in cells treated with selective compounds under hypoxia and HRE interaction.