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Synthesis and evaluation of new macrocyclic compounds based on jatrophane scaffold

Final Report Summary - MDR MODULATOR (Synthesis and evaluation of new macrocyclic compounds based on jatrophane scaffold)

Synthesis and evaluation of new macrocyclic compounds based on jatrophane scaffold

Summary description of the project objectives:

1) Approach to the synthesis of new Multi Drug Resistance modulator
2) Preparation of natural product analogues and their evaluation as Multi Drug Resistance modulator
3) Biologically evaluation of chemically synthesized natural product analogues as anti-metastatic agents

Description of the work performed since the beginning of the project and main results achieved so far.

The occurrence of resistance to anticancer agents is a major obstacle for successful cancer chemotherapy. The emergence of resistance to anticancer drugs, in particular multidrug resistance (MDR) has made many of the available anticancer drugs ineffective. (1) MDR, is a complex multifactorial phenomenon that can result from a number of biochemical mechanisms. One of these possible mechanisms is the enhanced activity of various members of a family of (ABC)-transporters. ABCB1, also known as P-glycoprotein, transport the drug from inside to the outside of the cell. This reduces the cytotoxicity of the anticancer agent and enables the tumour cells to survive. MDR problem could be overcome by the inhibition of this transport system. (2)

Jatrophane diterpene are a class of natural compounds, which were extracted from plants of the genus of Euphorbia. The phytopharmacological properties of the genus Euphorbia are well documented. A broad range of biological properties have been reported for constituents of the plant extract. (3) In particular, jatrophane have been found to be potent and specific P-glycoprotein modulators. (4)

Our goal is to prepare new synthetic jatrophane analogues with an increased biological activity. As starting material, we decided to use the inexpensive monosaccharide L-sorbose. This monosaccharide is the starting material for the industrial synthesis of Vitamin C. Its production is approximately 60000 tons/year. Despite the similarity with the well exploited D-fructose, only a few methods have been developed for the modification of this readily available sugar. We decided to develop a new manipulation strategy and we applied this methodology for the preparation of an advanced intermediate that can be used for the preparation of a library of jatrophone analogues

Final results and their potential impact and use

A novel synthetic approach for the manipulation of L-sorbose was developed. An advanced intermediate for the preparation of potential Multi Drug Resistance Modulators was synthesized. Importantly, the synthetic route developed herein provided access to cyclopentitols (polyhydroxylated cyclopentanes) which are of particular significance because of their presence in a variety of medicinally relevant natural products.

The synthetic route developed herein is expected to have a significant impact in the scientific community devoted to use of monosaccharides and their application in synthesis. The research is related to the use of materials from the chiral pool for synthesis.

Synthesis of Migrastatin analogues.

Migrastatin analogues were synthesized in order to evaluate their biological property as Multi Drug Resistance modulators (inhibitors of Pgp). For this purpose, we developed a novel synthetic route for the preparation of migrastatin-core analogues. Unfortunately, migrastatin analogues failed to inhibit Pgp. For this reason, the synthesized compounds were also tested as inhibitors of cell migration, an important target in cancer metastasis.

Biological evaluation of Migrastatin analogues.

Cell migration is involved in several physiological processes. On other hand, cell migration is also involved in other pathological processes such as metastasis. (5) Synthesized migrastatin analogues were found to inhibit cell migration in human breast cancer and canine cancer cell lines. (6) In collaboration with researchers at the Beatson Institute in Glasgow, we observed that in vivo migrastatin analogue treatment enhance cell-cell adhesion and therefore antagonize metastasis. (7)

Final results and their potential impact and use

In conclusion, we develop a scalable route for the preparation of migrastatin-core analogues. We also provided materials to collaborators who carried out a study in vivo related to the mechanism by which this class of compounds inhibits tumour cell migration. We expect that these results have significant impact in the scientific community devoted to the study of cancer metastasis and cell migration in pathological conditions.

References

(1) Borowski, E.; BontempsGracz, M.; Piwkowska, A. Acta Biochim. Pol., 2005, 52, 609.
(2) Robert, J.; Jarry, C. J. Med. Chem. 2003, 46, 4805.
(3) Hiller, K.; Melzig, M. F. Lexikon der Arzneipflanzen und Drogen; Spektrum Akademischer Verlag: Heidelberg, Germany, 1999.
(4) (a) Corea, G.; Fattorusso, E.; Lanzotti, V.; Taglialatela-Scafati, O.; Appennino, G.; Ballero, M.; Simon, P. -N.; Dumontet, C.; Di Pietro, A. J. Med. Chem. 2003, 46, 3395; (b) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon, P. -N.; Dumontet, C.; Pietroio, A. D.; Planta Med. 2004, 70, 657; (c) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon, P.-N.; Dumontet, C.; Di Pietro, A. J. Med. Chem. 2004, 47, 988; (d) Barile, E.; Borriello, M.; Pietro, A. D.; Doreau, A.; Fattorusso, C.; Fattorusso, E.; Lanzotti, V. Org. Biomol. Chem. 2008, 6, 1756–1762.
(5) Carmeliet, P.; Nat. Med. 2003, 9, 653.
(6) Majchrzak, K.; Lo Re, D.; Gajewska, M.; Bulkowska, M.; Homa, A.; Pawłowski, K.; Motyl, T.; Murphy, P.; Król, M. PlosOne, 2013, 8, e76789.
(7) Lo Re, D.; Zhou, Y.; Nobis, M.; Anderson, K.; Murphy, P.V. ChemBioChem, 2014, 15, 1459.