Cancer is a group of diseases that can affect any part of the body via an uncontrolled and anomalous cellular proliferation. In this research field, the tumor protein p53 is a widely-studied therapeutic target in cancer treatment, as this transcription factor is inactivated in all types of human cancers. In 50% of malignancies, p53 is found expressed in its wild-type form and generally inhibited by two major negative regulators, MDM2 and MDMX. In the remaining 50% of cases, p53 is inactivated by contact and conformational mutations principally on its DNA-binding site, thus not exercising its regulatory function. [1] In the last years, our research group has been actively involved in the synthesis of small molecules to reactivate the p53 pathway. Starting from the enantiopure aminoalcohol tryptophanol, we have recently developed several small molecules that reactivate p53 (Figure 1). Here we present our most updated results on the development of a chemical library of (S)- and (R)-tryptophanol-derived oxazoloisoindolinones. This class of compounds may be accessed by cyclocondensation reaction of enantiopure forms of tryptophanol and several achiral oxoacids. In this synthetic approach, the chiral inductor (tryptophanol) is responsible for the stereo-outcome of the final product and it is part of the main skeleton of the bioactive molecules. For those reasons, this asymmetric reaction is highly efficient/atom economic. Interestingly, this specific one-step synthetic strategy allows to the construction of a new chiral center. [2] From this work tryptophanol-derived bicyclic lactams SLMP53-1 and DIMP53-1 were identified as the most promising p53 reactivators. [3] Further hit-to-lead optimization is ongoing, and assessment of the antiproliferative activity of the optimized oxazoloisoindolinones against four different cancer cells lines highlights that this chemical family displays selectively potent antitumor activity towards p53 with no apparent toxic effects.

Acknowledgements

Fundação para a Ciência e a Tecnologia (FCT) through PTDC/DTP-FTO/1981/2014, PTDC/QUI-QOR/29664/2017, UID/DTP/04138/2013, PD/BI/135334/2017 and IF/00732/2013.

References

[1]. Espadinha M, Barcherini V, Lopes E A, Santos M M M (2018). Curr Top Med Chem 18: 647-60.

[2]. Dourado J, Pérez M, Griera R, Santos M M M (2016). RSC, Chapter 3.1.19, 198-201.

[3]. a) Soares J, Raimundo L, Pereira N A L, Monteiro A, Gomes S, Bessa C, Pereira C, Queiroz G, Bisio A, Fernandes J, Gomes C, Reis F, Gonçalves J, Inga A, Santos M M M, Saraiva L (2016). Oncotarget 7(4): 4326-43; b) Soares J, Espadinha M, Raimundo L, Ramos H, Gomes A S, Gomes S, Loureiro J B, Inga A, Reis F, Gomes C, Santos M M M, Saraiva L (2017). Molecular Oncology 11(6): 612-27.