Final Report Summary - VVINCANCER (Novel vinca alkaloids analogues as anticancer agents: a multidisciplinary quest)
Cancer remains an important public health problem worldwide. Despite the advancement obtained thanks to prevention and early diagnosis, the fight against cancer is far to be won. In particular, toxicity, efficacy and selectivity of the chemotherapeutics still represent a severe challenge which can be tackled by new scientific findings in tumour treatment. Natural compounds have always played an essential role in anticancer therapy; remarkably, the 79.8 % of the new chemical entities approved for antitumour use from 1981 to 2006 were classified as naturally derived or inspired. Furthermore, the chemical synthesis of analogues of natural products may be the key for accessing innovative drugs, with improved potency at small doses, lower side-effects and increased selectivity.
In particular, the alkaloids - a nitrogen-rich class of natural products - are already used routinely in cancer therapy. For example, the vinca alkaloid Vinblastine, a natural product isolated from the Madagascar periwinkle plant has been widely used in the clinic as anti-tumour drug since the early 1960s; it induces cell death by binding tubulin and, therefore, interfering with microtubule formation in mitosis. To develop new anti-cancer drugs, especially against resistant cell lines, it will be essential to be able to modify efficiently the structure of the natural products. Unfortunately, the extreme complexity of the natural products makes their synthesis highly challenging and new chemical methods are urgently needed to access efficiently these compounds.
In this project, the goal was to use the exceptional reactivity of aminocyclopropanes in cyclisation and annulation reactions for the synthesis of bioactive alkaloids and their analogues. In particular, it was envisioned that the development of new catalytic methods would give access to complex targets efficiently under mild conditions.
Cyclisation reactions were first used in an attempt to synthesise Vinblastine. Although important progress was realised using different synthetic strategies, the natural product could not yet be accessed using the developed methodology. Nevertheless, important knowledge has been gained about the possibilities and limitation of the method, and bases have been set for future campaigns towards the synthesis of natural alkaloids.
In the second part of the project, we focused on the investigation of the chemical behaviour of aminocyclopropanes in (3+2) annulation reactions. The research culminated in the development of the first catalytic protocols for the (3+2) annulation of aminocyclopropanes with aldehydes and ketones. This (3+2) reaction allows the one-pot, atom-economic assembly of 2-aminotetrahydrofurans, a common motif in 'evolutionarily selected' molecules such as nucleosides, as well as in synthetic drugs such as AZT. It is well-known that nucleosides and their mimetics are widespread as therapeutic agents for the treatment of cancer, infections and viral diseases. Therefore, the 2-aminotetrahydrofuran core may be rightly considered as a privileged scaffold for drug discovery. Accordingly, the new chemical entities obtained by this innovative method are going to be tested against a variety of biological targets in collaboration with groups working in biology.
In conclusion, we have confirmed that aminocyclopropanes are indeed versatile building blocks for the synthesis of the core of bioactive compounds. Unprecedented chemical entities based on tetrahydrofurylamines could be already accessed using the methodology. The bases are now set to use the developed tools for the synthesis of natural products or libraries of bioactive compounds. It remains certain, however, that the chemistry of aminocyclopropanes has just begun to be investigated, and continuing research in fundamental organic chemistry will be essential in the future to fully exploit their synthetic potential.
In particular, the alkaloids - a nitrogen-rich class of natural products - are already used routinely in cancer therapy. For example, the vinca alkaloid Vinblastine, a natural product isolated from the Madagascar periwinkle plant has been widely used in the clinic as anti-tumour drug since the early 1960s; it induces cell death by binding tubulin and, therefore, interfering with microtubule formation in mitosis. To develop new anti-cancer drugs, especially against resistant cell lines, it will be essential to be able to modify efficiently the structure of the natural products. Unfortunately, the extreme complexity of the natural products makes their synthesis highly challenging and new chemical methods are urgently needed to access efficiently these compounds.
In this project, the goal was to use the exceptional reactivity of aminocyclopropanes in cyclisation and annulation reactions for the synthesis of bioactive alkaloids and their analogues. In particular, it was envisioned that the development of new catalytic methods would give access to complex targets efficiently under mild conditions.
Cyclisation reactions were first used in an attempt to synthesise Vinblastine. Although important progress was realised using different synthetic strategies, the natural product could not yet be accessed using the developed methodology. Nevertheless, important knowledge has been gained about the possibilities and limitation of the method, and bases have been set for future campaigns towards the synthesis of natural alkaloids.
In the second part of the project, we focused on the investigation of the chemical behaviour of aminocyclopropanes in (3+2) annulation reactions. The research culminated in the development of the first catalytic protocols for the (3+2) annulation of aminocyclopropanes with aldehydes and ketones. This (3+2) reaction allows the one-pot, atom-economic assembly of 2-aminotetrahydrofurans, a common motif in 'evolutionarily selected' molecules such as nucleosides, as well as in synthetic drugs such as AZT. It is well-known that nucleosides and their mimetics are widespread as therapeutic agents for the treatment of cancer, infections and viral diseases. Therefore, the 2-aminotetrahydrofuran core may be rightly considered as a privileged scaffold for drug discovery. Accordingly, the new chemical entities obtained by this innovative method are going to be tested against a variety of biological targets in collaboration with groups working in biology.
In conclusion, we have confirmed that aminocyclopropanes are indeed versatile building blocks for the synthesis of the core of bioactive compounds. Unprecedented chemical entities based on tetrahydrofurylamines could be already accessed using the methodology. The bases are now set to use the developed tools for the synthesis of natural products or libraries of bioactive compounds. It remains certain, however, that the chemistry of aminocyclopropanes has just begun to be investigated, and continuing research in fundamental organic chemistry will be essential in the future to fully exploit their synthetic potential.