Antitumoral natural products

Microtubule stabilizers. Tubulin is an established target of clinical anticancer drugs, including both microtubule-stabilizing agents and tubulin polymerization inhibitors. Most of our work on tubulin modulators over the last few years has focused on the bacterial macrolides epothilones.

The major objectives of this research were (i) to continuously advance our basic understanding of the structural requirements for bioactivity, and (ii) to explore the biologically tolerated scope for gross structural changes, in order to develop hypermodified analogs that would represent new chemotypes of microtubule-stabilizing agents (and hence new lead structures for anticancer drug discovery) (Feyen et al., 2008) In the course of this work, we have created highly modified epothilones which proved to have similar antiproliferative activity as the natural products epothilones A/B. This includes hypermodified analog 2, which inhibits cancer cell proliferation in vitro with single digit nM IC50 values.[2] The synthesis of this analog features a stereoselective cyclopropanation reaction and a highly efficient ring-closure by RCM (Kuzniewski et al., 2008).

While the hypermodified analogs above still incorporate a fully polyketide-based macrolactone core, we have also investigated structures that are characterized by a disruption of the regular polyketide backbone through the replacement of C12 by a nitrogen atom. Depending on the nature of the N12 substituent, the tubulin-polymerizing and antiproliferative activity of the corresponding 12-aza-epothilones (”azathilones”) are comparable with epothilone A, e. g. for analog 3 (Feyen et al., 2006). We have developed two synthetic approaches to these analogs, one being based on ring closure through RCM.

The SAR of 12-aza-epothilones is distinctly different from that of natural epothilones and we are currently investigating whether these findings reflect differences in the bioactive conformation between azathilone-type analogs and natural epothilones (in a collaboration with Dr. J. Fernando Dìaz and Prof. J. A. Jimenez-Barbero, CISC, Madrid, Spain). Our most recent work on epothilones has focused on the design and synthesis of new functionalized analogs (including new hypermodified analogs) that will be employed in the construction of tumor-targeted prodrugs and antibody-drug conjugates (ADCs) (in collaboration with Prof. D. Neri, ETHZ).

In addition to our work on epothilones, we have recently completed a new, efficient total synthesis of the marine natural product (-)-zampanolide and the corresponding side chain-free non-natural product (-)-dactylolide (Zurwerra et al., 2010).

In collaboration with Dr. J. Fernando Dìaz, CISC, Madrid, Spain, we have confirmed and extended recent literature findings on the interactions of (-)-zampanolide with microtubules. Based on a sufficient supply of material from our synthetic work the group of Dr. Dìaz was able to show that both (-)-zampanolide as well as (-)-dactylolide bind to microtubules in a covalent fashion and they have also identified the amino acid that is modified by these ligands (unpublished data).
Other lead structures that are pursued in the area of tubulin modulators are peloruside A, where we are preparing simplified analogs such as 4 (Wullschleger et al., 2010). Work along these lines is still ongoing.

Feyen, F., Cachoux, F., Gertsch, J., Wartmann, M., Altmann, K.-H., Epothilones as Lead Structures for the Synthesis-Based Discovery of New Chemotypes for Microtubule Stabilization. Acc. Chem. Res. 2008, 41, 21-31.

Feyen, F., Gertsch, J., Wartmann, M., Altmann, K.-H., Design and synthesis of 12-aza-epothilones (azathilones) – Non-natural natural products with potent anticancer activity. Angew. Chem. Int. Ed. 2006, 45, 5880-5885.

Kuzniewski, C. N., Gertsch, J., Wartmann, M., Altmann, K.-H., Total Synthesis of Hypermodified Epothilone Analogs with Potent in vitro Antitumor Activity. Org. Lett. 2008, 10, 1183-1186.

Wullschleger, C. W., Gertsch, J., Altmann, K.-H., Stereoselective Synthesis of a Monocyclic Peloruside A Analogue. Org. Lett. 2010, 12, 1120-112.

Kinase Inhibitors. Kinases have emerged as important drug targets for cancer treatment, with currently 11 different kinase inhibitors in clinical use as anticancer drugs. While the majority of these agents (as well as others currently in clinical development) are low-molecular-weight synthetic molecules based on different types of heteroaromatic or urea scaffolds, a number of naturally occurring resorcylic acid lactones (RAL) have recently emerged as alternative new lead structures for kinase inhibition. This group of NPs comprises the fungal metabolites hypothemycin, LL-Z1640-2, radicicol A, and L-783277. All of these NPs incorporate a cis-enone moiety as part of their macrolactone ring; as has been shown for hypothemycin the enone system acts as a 1,4-acceptor for an active site Cys residue that is present only in a subset of kinases (comprising ca. 10% of the human kinome), but that includes a number of disease-relevant kinases such as VEGFR-R, Flt-3, or Mek.

We have established the first total synthesis of the RAL L-783277 and in collaboration with researchers at the Novartis Institute for Biomedical Research in Basel we have delineated the inhibition profile of the compound against 35 different kinases (Hofmann et al., 2008).

In a subsequent step we have prepared a small number of analogs that have addressed the importance of key functional groups in the natural product; this limited SAR study has provided important guidance for the design of future analogs (Liniger et al., 2011).

Hofmann, T., Altmann, K.-H., Total Synthesis of the Resorcylic Lactone-based Kinase Inhibitor L-783277. Synlett, 2008, 1500-1504.

Liniger, M., Neuhaus, C., Hofmann, T., Fransioli-Ignazio, L., Jordi, M., Drueckes, P., Trappe, J., Fabbro, D., Altmann^, K.-H. Kinase Inhibition by Deoxy Analogs of the Resorcylic Lactone L-783277. ACS Med. Chem. Lett., 2011, 2, 22-27.

NPs with unknown mechanisms. We have established a highly efficient total synthesis of the bicyclic Xenia diterpenoid blumiolide C, which features the RCM-based closure of a 9-membered ring in an oxa-bicyclo[7.4.0]tridecane system (Hamel et al., 2009).

While blumiolide C had been reported to be a potent antiproliferative agent, unfortunately, the literature data on the biological activity of this specific compound could not be confirmed. Exploratory activities on the synthesis of other Xenia diterpenoids continue in the group, however, in order to develop a broader understanding of this class of marine natural products.

Hamel, C., Prusov, E., Gertsch, J., Altmann, K.-H., Total synthesis of blumiolide C. Angew. Chem. Int. Ed., 2008, 47, 10081.