Periodic Reporting for period 2 - CoSyMoDe (Cooperative Synthesis by Molecular Deconvolution)
Reporting period: 2023-07-01 to 2024-12-31
The CoSyMoDe action is entitles „Cooperative Synthesis by Molecular Deconvolution”. It addresses the lack of tools in Organic Synthesis to construct complex and intricate molecular structures – specifically small molecules – efficiently. In the usual case, the pursuit for a complex structure over-proportionally increases the synthetic affort required to access it synthetically. This inability of organic chemistry is strongly hampering the use of such complex e.g. 3-dimensional small molecules in pharmaceutical applications to date – leaving the better part of this industry with heterocyclic aromatic compounds to investigate. The latter compounds being flat (2-dimansional) and thus often lack selectivity when interacting with biological targets. The confinement to these 2-dimensional compunds strongly narrows down potential drug candidates and is slowing down chemical innovation in the field. The reason for the reluctance of pharmaceutical industry to carry out research on 3-dimensional complex molecules is the fact that synthetic complications get quickly in the way and require time, personnel and thus render the whole process unattractive due to mal ROIs (return of investments). As a consequence, industry deprives itself from target molecules that interact very selectively and specifically with biological targets – because 3-dimensional complex structures provide all these features making them ideal targets for pharmaceutical research. CoSyMode therefore addresses an important societal issue that obtained much public attention but prevailed for decades before already – the dependence of the EU on drug manufacturers of third party countries such as PR China and India. The pandemic and the months after that painfully brought this to light and urgently need to be solved. CoSyMoDe addresses this problem in so far as it provides an alternative to make 3-dimensional complex molecules efficiently accessible via organic chemistry and ease the use of their application for chemical industry. This will provide opportunities for innovation, new patents and lower the dependence of the EU on imports since an increased ROI allows companies to retain their manufacturing capacities within the EU were higher overall production costs prevail in comparison to the mentioned third-party countries.
The work performed in this reporting time involves the prove of concept which was accomplished in so far as the key reactions (fragmentation reactions) were successfully implemented.The taxane natural product family to which the the chemistry was applied is a well known natural product family and marketed since more than 30 years in cancer treatment. We were able to synthesize the most complex congener canataxpropellane andconvert the scaffold of this molecule into the backbones of the other family congeners. We are now dedicated to implement those findings to access the other taxane diterpene natural products efficiently to provide materialfor their pharmaceutical evaluation - a task previously impossible to accomplish due to lack of isolated material from natural sources.
Within the research program of CoSyMoDe we have found, that besides the attempted and successfully executed fragmentations of the required carbon-carbon bonds in a selective fashion we can take this strategic concept far beyond the application to complex taxane structures. In fact we are capable to carry out on demand fragmentation of virtually every single carbon-carbon bond on demand. We are therefore capable to extend the de-convolution of cyclotaxanes to completely structurally unrelated scaffolds which exhibit complex 3-dimensional molecular backbones. This strategic access now paves the way for creating novel structurally and functionally complex small molecules for drug development and provide the opportunity to escape flatland in drug design in a rationale manner since from a single intricate scaffold very variable backbones are created in a rationale manner and readily available for drug development. This synthetic startegy has therefore the potential to close the gap on this long-standing issue in drug development by accessing a broad chemical space previously unexplored for drug design. A selection of structures of such 3-dimensional complexity that we have made accessible so far is depicted in Figure 1 and illustrates the architectural features of theses compounds which are currently tested for their biological activity. We are currently expanding the scope and number of potential fragmentation events to diversify the portfolio of structures and show that a strategically employed fragmentation strategy can be sought after in general when creating 3D-compound libraries for drug development in order to escape flatland.