Alexander Dömling

Chemistry and Biology Of Multicomponent Reactions

Alexander Dömling,*,†,‡ Wei Wang,†,§ and Kan Wang† †Department of Pharmaceutical Sciences, University of Pittsburgh, Biomedical Science Tower 3, Suite 10019, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, United States ‡Chair of Drug Design, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, P. R. China

MULTICOMPONENT REACTIONS IN ORGANIC-CHEMISTRY

Traditionally, organic syntheses are effected by a sequence of reactions between two components: one consequence of this is that final yields can be very low. It has long been known, however, that effective syntheses can be carried out using three, or sometimes more, reactants simultaneously and a few such processes are used industrially. In recent years processes of this kind have been systematically investigated using sophisticated computer techniques, and successful syntheses have been achieved using as many as seven components.

Multikomponentenreaktionen mit Isocyaniden

Multikomponentenreaktionen (MCRs) unterscheiden sich in mehreren Aspekten grundlegend von Zweikomponentenreaktionen. Unter den MCRs haben sich solche mit Isocyaniden in der pharmazeutischen Industrie zu popularen organisch-chemischen Reaktionen zur Herstellung von Substanzbibliotheken aus niedermolekularen wirkstoffartigen Verbindungen entwickelt. Mit einem kleinen Set von Ausgangsverbindungen konnen in kurzer Zeit sehr grose Bibliotheken aufgebaut und fur Fragestellungen in der Wirkstoff-Forschung verwendet werden. Aufgrund der intensiven Forschung der letzten Jahre sind viele neue Strukturtypen zuganglich geworden. Vermehrt werden MCRs auch in der Totalsynthese von Naturstoffen eingesetzt. MCRs und insbesondere MCRs mit Isocyaniden bieten viele Moglichkeiten, zu neuen Reaktionen und Grundgerusten zu gelangen. Dies setzt jedoch voraus, dass der Chemiker die „Sprache“ der MCRs lernt, wozu dieser Ubersichtsartikel anregen soll.

The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries

The first century of isocyanide chemistry, which was then still a rather empty part of Organic Chemistry, began in 1859. In 1958 isocyanides became generally available by dehydration the formylamines. One year later the four component reaction of isocyanides (U-4CR) was introduced. This one-pot reaction is accomplished just by mixing amines, carbonyl compounds, suitable acids and isocyanides. Most chemical reactions have their own ”scope and limitation”, whereas the U-4CR can convert almost all combinations of educts into their products. Until 1995 this chemistry was moderately used, but since then a new era of the U-4CR and its unions with further reactions have become increasingly popular, particularly as libraries. In industry this chemistry became one of its most often used methods of finding new desirable products. In contrast to most other areas of chemistry, isocyanide chemistry is not yet exhausted and still much progress can be expected there.

Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery

Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.

The discovery of new isocyanide-based multi-component reactions

Multi-component reactions are finding increasing use in the discovery process of new drugs and agrochemicals. Some years ago they were considered as highly exotic types of organic reactions. Recently, many groups have realized that the field of multi-component reactions is full of new opportunities. These comprise fast and efficient production of small-molecular-weight compound libraries, highly atom-economic chemistry, very large chemical libraries, improvements in total synthesis, and applications in bioconjugate chemistry, as well as in related fields (e.g. chemical biology).

Small molecular weight protein–protein interaction antagonists—an insurmountable challenge?

Several years ago small molecular weight protein-protein interaction (PPI) antagonists were considered as the Mount Everest in drug discovery and generally regarded as too difficult to be targeted. However, recent industrial and academic research has produced a great number of new antagonists of diverse PPIs. This review structurally analyses small molecular weight PPI antagonists and their particular targets as well as tools to discover such compounds. Besides general discussions there will be a focus on the PPI p53/mdm2.

Survivin Is a Therapeutic Target in Merkel Cell Carcinoma

A targeted therapy for a virus-induced cancer involves blockade of the cellular oncoprotein survivin. Targeting a Hijacked Protein Some have expressed disappointment that the Human Genome Project has not delivered more on its promise to find causes and cures for diseases such as cancer. Until recently, Merkel cell carcinoma (MCC) had no known etiology and few treatment options beyond surgery and irradiation. MCC, an aggressive nonmelanotic human skin cancer, is most commonly found in elderly and immunosuppressed populations, suggesting a possible viral cause. In 2008, a transcriptomic technology based on genomics revealed a new virus, Merkel cell polyomavirus (MCV), that causes ~80% of MCC. In a new study, Arora et al. now identify the molecular pathway that is activated in MCC cells by this virus. When the authors deleted viral oncoproteins called T antigens expressed in MCV-infected MCC cells, they found that a key cellular protein, survivin, also disappeared and the MCC cells died. Survivin mRNA expression is controlled by the MCV large T antigen, which binds to the cell cycle regulator retinoblastoma protein. Activation of the survivin gene by MCV was confirmed using the same transcriptome data set that was originally used to identify this virus. Survivin has been implicated in other cancers and is known to confer chemotherapy resistance on tumors. This cellular oncoprotein can be targeted by an imidazole small-molecule inhibitor called YM155 that has entered phase 2 trials for treating certain cancers. Arora et al. show that YM155 at nanomolar concentrations preferentially killed MCC cells infected with MCV. In contrast, of 1360 other compounds screened, only one other chemotherapeutic drug (bortezomib) showed similar potency. When human MCC tumors were grown in immunodeficient mice as xenografts, YM155 halted tumor growth and prolonged mouse survival during short-term treatment. These new findings demonstrate how genomic data can be applied to help identify the cause of a cancer and thus point the way to new targets that can be exploited therapeutically. Merkel cell polyomavirus (MCV) causes ~80% of primary and metastatic Merkel cell carcinomas (MCCs). By comparing digital transcriptome subtraction deep-sequencing profiles, we found that transcripts of the cellular survivin oncoprotein [BIRC5a (baculoviral inhibitor of apoptosis repeat-containing 5)] were up-regulated sevenfold in virus-positive compared to virus-negative MCC tumors. Knockdown of MCV large T antigen in MCV-positive MCC cell lines decreased survivin mRNA and protein expression. Exogenously expressed MCV large T antigen increased survivin protein expression in non-MCC primary cells. This required an intact retinoblastoma protein–targeting domain that activated survivin gene transcription as well as expression of other G1-S–phase proteins including E2F1 and cyclin E. Survivin expression is critical to the survival of MCV-positive MCC cells. A small-molecule survivin inhibitor, YM155, potently and selectively initiates irreversible, nonapoptotic, programmed MCV-positive MCC cell death. Of 1360 other chemotherapeutic and pharmacologically active compounds screened in vitro, only bortezomib (Velcade) was found to be similarly potent, but was not selective in killing MCV-positive MCC cells. YM155 halted the growth of MCV-positive MCC xenograft tumors and was nontoxic in mice, whereas bortezomib was not active in vivo and mice displayed serious morbidity. Xenograft tumors resumed growth once YM155 treatment was stopped, suggesting that YM155 may be cytostatic rather than cytotoxic in vivo. Identifying the cellular pathways, such as those involving survivin, that are targeted by tumor viruses can lead to rapid and rational identification of drug candidates for treating virus-induced cancers.

Biological evaluation of tubulysin A: A potential anticancer and antiangiogenic natural product

Tubulysin A (tubA) is a natural product isolated from a strain of myxobacteria that has been shown to depolymerize microtubules and induce mitotic arrest. The potential of tubA as an anticancer and antiangiogenic agent is explored in the present study. tubA shows potent antiproliferative activity in a panel of human cancer cell lines irrespective of their multidrug resistance properties. It induces apoptosis in cancer cells but not in normal cells and shows significant potential antiangiogenic properties in several in vitro assays. It is efficacious in initial animal studies using a hollow fibre assay with 12 different human tumour cell lines. This study suggests that both in vitro and preclinical profiles of tubA may translate into clinically useful anticancer properties.

Robust Generation of Lead Compounds for Protein–Protein Interactions by Computational and MCR Chemistry: p53/Hdm2 Antagonists†

The discovery of a lead compound is an essential process in early drug discovery, hopefully eventually resulting into a clinical candidate and a drug for the treatment of a disease. Besides affinity and selectivity for the target, however, other target unrelated compound properties are equally important for the fate of drug candidate, e.g. water solubility, lipophilicity and molecular weight since they determine important aspects such as oral bioavailability, dosing schedule and side effects. The parallel discovery and early development of several leads is therefore now pursued whenever possible, an approach that takes into account the high attrition rate of early drug discovery projects. Currently, hits as starting points for medicinal chemistry optimisations are mostly found by high-throughput screening (HTS) campaigns and to a much less extent by structure-based approaches including fragment-based and computational drug discovery. For certain target classes, however, HTS often yields very low numbers of hits.[1] For example, protein-protein interactions (PPIs) are notoriously difficult to hit with drug-like small molecules.[2] This has been assigned to the unusual structure, topology and flexibility of protein-protein interfaces.[3] The recent advancement of several drugs into clinical development clearly shows that certain PPIs, e.g., Bcl-x and XIAP, can be efficiently targeted by small molecules.[4] Here, we describe a complementary process that led to the parallel discovery of several compounds belonging to seven different scaffold classes, amenable to synthesis by efficient multicomponent reaction (MCR) chemistry in just one step, that antagonize the PPI between the transcription factor p53 and its negative regulator Hdm2.