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Natural Products as Lead Structures for Anticancer Drug Discovery: Synthesis and SAR of Rhizoxin Analogs

English title Natural Products as Lead Structures for Anticancer Drug Discovery: Synthesis and SAR of Rhizoxin Analogs
Applicant Altmann Karl-Heinz
Number 143269
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Organic Chemistry
Start/End 01.01.2013 - 31.08.2013
Approved amount 86'953.00
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Keywords (6)

Rhizoxin; SAR; Natural product synthesis; Drug discovery; Cancer; Natural products

Lay Summary (German)

Lead
Lay summary

Rhizoxin ist ein von Bakterien produzierter Naturstoff, der die Vermehrung von Krebszellen im Reagenzglas wie auch das Wachstum von Tumoren in Tiermodellen potent unterdrücken kann. Es wurde ursprünglich angenommen, dass die Substanz von Pilzen der Gattung Rhizopus produziert wird, die als Verursacher der Reiskeimlingsfäule gelten, neuere Studien haben jedoch gezeigt, dass Rhizoxin aus Bakterien stammt, die mit diesen Pilzen in Symbiose leben. Aufgrund seiner interessanten Antitumorwirkung wurde Rhizoxin bereits in einer Reihe von klinischen Studien am Menschen als mögliches Krebsmedikament untersucht. Diese Studien wurden jedoch wegen eines ungünstigen Verhältnisses zwischen therapeutischem Effekt und Toxizität in Phase II eingestellt. Es ist aber ohne weiteres denkbar, dass strukturelle Abwandlungen des Naturstoffs zu Substanzen mit verbesserten Eigenschaften führen könnten. Solche Analoga sind prinzipiell entweder de novo durch chemische Synthese oder aber durch chemische Derivatisierung des Naturstoffs zugänglich. Im letzteren Fall muss dieser natürlich in ausreichenden Mengen zur Verfügung stehen.

Die chemische Synthese des Rhizoxins ist bereits in der Vergangenheit untersucht worden; desgleichen wurden gewisse Studien zum Zusammenhang zwischen der Struktur des Moleküls und biologischer Aktivität (sog. SAR, oder „structure-activity relationship“, Studien) durchgeführt. In beiden Bereichen lassen die bisherigen Studien jedoch wichtige Fragen offen. Wir haben im bisherigen Verlauf dieses Forschungsprojekts einen neuartigen synthetischen Zugang zum Rhizoxin entwickelt. Die hierbei entwickelte Methodik setzen wir nun für die Synthese neuer Analoga für systematische SAR Studien ein. Letztere sollen die Beantwortung wichtiger Fragen erlauben, die bis anhin nur unzulänglich geklärt sind. Auf diese Weise wird dieses Forschungsprojekt zu einem verbesserten Verständnis der Struktur-Wirkungs-Beziehungen rund um das Rhizoxin führen. Die daraus gewonnen Erkenntnisse könnten dann die Grundlage für die Entwicklung von neuen Wirkstoffkandidaten bilden, die vielleicht ein gegenüber dem Rhizoxin verbessertes therapeutisches Potenzial aufweisen könnten.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Total Synthesis of the Tubulin Inhibitor WF-1360F Based on Macrocycle Formation through Ring-Closing Alkyne Metathesis
Neuhaus Christian M., Liniger Marc, Stieger Martin, Altmann Karl-Heinz (2013), Total Synthesis of the Tubulin Inhibitor WF-1360F Based on Macrocycle Formation through Ring-Closing Alkyne Metathesis, in ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 52(22), 5866-5870.

Collaboration

Group / person Country
Types of collaboration
Basilea Pharmaceutica Switzerland (Europe)
- Publication
Dr. Michel Steinmetz Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. José Fernando Diaz Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
126511 Natural Products as Lead Structures for Anticancer Drug Discovery: Synthesis and SAR of Rhizoxin Analogs 01.01.2010 Project funding (Div. I-III)
149253 Natural Products as Lead Structures for Anticancer and Antibacterial Drug Discovery: SAR Evaluation of Zampanolide and Pyridomycin 01.04.2014 Project funding (Div. I-III)
175744 Natural Products as Lead Structures for Anticancer and Antibacterial Drug Discovery: SAR Evaluation of Zampanolide and Pyridomycin 01.10.2017 Project funding (Div. I-III)

Abstract

Rhizoxin (R-1) is a bacterial natural product that inhibits the polymerization of tubulin. As a consequence, it exhibits potent antiproliferative activity against cancer cells in vitro and in vivo, including cell lines and tumors that are multidrug-resistant. Rhizoxin (R-1) has been investigated in a number of Phase II clinical trials, but has not shown any relevant clinical efficacy. The reasons for the clinical failure of the compound are not well understood.The chemistry and SAR of rhizoxin (R-1) have been investigated in some detail, but important questions have remained unaddressed (or have not been addressed in a systematic way) at both levels. Thus, all total syntheses reported to date for either rhizoxin (R-1) or its naturally occurring variant rhizoxin D (R-2), with one single exception, have relied on macrolactonization through intramolecular Horner-Wittig-Emmons (HWE) reaction between C2 and C3. As part of the ongoing SNF project 200021_126511 we have investigated the possibility of macrocycle formation by ring-closing olefin metathesis (RCM) with different dienes, including, for example, A-28. However, the desired macrocycle could not be obtained at preparatively useful levels for any of the substrates and conditions investigated. In contrast, we found that diyne A-33 undergoes ring-closing alkyne metathesis (RCAM) to the desired 16-membered macrocyclic alkyne A-35 in good yield. Within the framework of our ongoing SNF project we will explore the suitability of A-35 as a precursor for the synthesis of 2,3-deoxy-rhizoxin (R-3), a naturally occurring rhizoxin variant which is virtually equipotent with R-1.However, the overall goal of this project is not limited to the synthesis of R-3, but also includes the synthesis of its side chain-modified analogs 1a-1e for SAR studies. These compounds (together with analogs 1f-1h, vide infra) were already proposed as synthesis targets for the ongoing SNF project 200021_126511. Due to objective difficulties with the envisioned RCM approach, however, none of these analogs has been obtained so far and it will not be possible to complete their synthesis within the remainder of the funding period of project 200021_126511 (which ends on Dec. 31st, 2012). Using appropriately modified versions of alkyne A-33, RCAM will also be employed for the synthesis of 1e, a 2,3-dehydro variant of R-1 (1f) and a lactam based analog (1h). As the sole exception, the synthesis of a 9,10-dehydro variant of R-1 (1g) will not be RCAM-based, but will involve ring closure through macrolactonization or intramolecular HWE reaction. We have solid preliminary data that indicate that the elaboration of A-35 into R-3 should be possible; however, should this not be the case on a preparatively useful scale, then other options for the synthesis of the desired target structures will be explored.All compounds will be assessed for their ability to inhibit tubulin polymerization and the growth of human cancer cell in vitro. In this context, analogs 1a-e will explore the activity of rhizoxin variants with intermediate side chain length and different polarity of the side chain terminus, while 1f and 1g will shed light on the significance of the geometric constraints imposed by the double bonds at C2/C3 and C9/C10 for bioactivity. Lactam 1h may offer enhanced metabolic stability.Overall, the studies proposed in this grant application will help to expand our basic understanding of both the synthetic chemistry and the SAR of rhizoxin (R-1). As such they could provide the basis for the development of new rhizoxin analogs with improved pharmacological properties over the original natural product lead.
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