ABSTRACT
The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/toxicity , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Benzothiazoles/toxicity , Humans , Protein Structure, Tertiary , Proto-Oncogene Proteins c-bcl-2/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/toxicity , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/toxicity , Urea/analogs & derivatives , Urea/chemistry , Urea/pharmacology , Urea/toxicity , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/chemistryABSTRACT
We have discovered a novel class of heterocyclic sulfonamides that act as antagonists of the S1P1 receptor. While members of this series identified from a high-throughput screen showed promising levels of potency in a cell-based assay measuring the inhibition of receptor internalization, most compounds were excessively lipophilic and contained an oxidation-prone thioether moiety. As a result, such compounds suffered from poor physical properties and metabolic stability, limiting their utility as in vivo probes. By removing the thioether group and systematically developing an understanding of structure-activity relationships and the effects of lipophilicity on potency within this series, we have been able to identify potent compounds with vastly improved physical properties. A representative enantiopure triazole sulfonamide (33) has measurable bioavailability following a low (3mg/kg) oral dose in rat, highlighting an achievement of the early hit-to-lead efforts for this series.
Subject(s)
Drug Discovery , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Receptors, Lysosphingolipid/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Heterocyclic Compounds/chemistry , Protein Binding/drug effects , Rats , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.
Subject(s)
Drug Design , Heterocyclic Compounds, 3-Ring/pharmacology , Inhibitor of Apoptosis Proteins/metabolism , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitor of Apoptosis Proteins/chemical synthesis , Inhibitor of Apoptosis Proteins/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.
Subject(s)
Antineoplastic Agents , Neoplasms , Rats , Animals , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met , Drug Design , Adenosine Triphosphate , Antineoplastic Agents/pharmacologyABSTRACT
A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.
Subject(s)
Amines/chemical synthesis , Drug Design , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/chemistry , Mitochondrial Proteins/chemistry , Piperidines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Apoptosis Regulatory Proteins , Biomimetics , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
Mechanisms to safely eliminate amyloids and preamyloid oligomers associated with many devastating diseases are urgently needed. Biophysical principles dictate that small molecules are unlikely to perturb large intermolecular protein-protein interfaces, let alone extraordinarily stable amyloid interfaces. Yet 4,5-dianilinophthalimide (DAPH-1) reverses Abeta42 amyloidogenesis and neurotoxicity, which is associated with Alzheimer's disease. Here, we show that DAPH-1 and select derivatives are ineffective against several amyloidogenic proteins, including tau, alpha-synuclein, Ure2, and PrP, but antagonize the yeast prion protein, Sup35, in vitro and in vivo. This allowed us to exploit several powerful new tools created for studying the conformational transitions of Sup35 and decipher the mechanisms by which DAPH-1 and related compounds antagonize the prion state. During fibrillization, inhibitory DAPHs alter the folding of Sup35's amyloidogenic core, preventing amyloidogenic oligomerization and specific recognition events that nucleate prion assembly. Select DAPHs also are capable of attacking preformed amyloids. They remodel Sup35 prion-specific intermolecular interfaces to create morphologically altered aggregates with diminished infectivity and self-templating activity. Our studies provide mechanistic insights and reinvigorate hopes for small-molecule therapies that specifically disrupt intermolecular amyloid contacts.
Subject(s)
Amyloid beta-Peptides/chemistry , Amyloid/chemistry , Peptide Fragments/chemistry , Phthalimides/chemistry , Prions/chemistry , Alzheimer Disease/metabolism , Biological Transport , Biophysics/methods , Cysteine/chemistry , Fluorescence Resonance Energy Transfer , Humans , Models, Biological , Peptide Termination Factors , Prions/metabolism , Protein Conformation , Protein Folding , Saccharomyces cerevisiae Proteins/metabolismABSTRACT
Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.
Subject(s)
Antineoplastic Agents , Dendrimers , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Dendrimers/chemical synthesis , Dendrimers/chemistry , Dendrimers/pharmacokinetics , Dendrimers/therapeutic use , Dogs , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, SCID , Neoplasms/metabolism , Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Rats , Rats, Wistar , Therapeutic Index , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , bcl-X Protein/antagonists & inhibitorsABSTRACT
Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , c-Mer Tyrosine Kinase/antagonists & inhibitors , Animals , Crystallography, X-Ray , Data Mining , Drug Discovery , Humans , Models, Molecular , c-Mer Tyrosine Kinase/chemistry , c-Mer Tyrosine Kinase/metabolismABSTRACT
Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
Subject(s)
Antineoplastic Agents/therapeutic use , Imidazoles/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Imidazoles/chemical synthesis , Male , Mice, Inbred C57BL , Mice, Nude , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins/metabolism , Pyridines/chemical synthesis , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , c-Mer Tyrosine Kinase/metabolism , Axl Receptor Tyrosine KinaseABSTRACT
PURPOSE: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2-selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL-mediated thrombocytopenia. EXPERIMENTAL DESIGN: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. RESULTS: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-xL-dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2-selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL-dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. CONCLUSIONS: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Hematologic Neoplasms/drug therapy , Piperidines/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Sulfones/pharmacology , Thrombocytopenia/drug therapy , bcl-X Protein/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Apoptosis , Benzamides/therapeutic use , Cell Proliferation , Female , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Piperidines/therapeutic use , Sulfones/therapeutic use , Thrombocytopenia/metabolism , Thrombocytopenia/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.
ABSTRACT
A novel series of covalent inhibitors of EGFR (epidermal growth factor receptor) kinase was discovered through a combination of subset screening and structure-based design. These compounds preferentially inhibit mutant forms of EGFR (activating mutant and T790M mutant) over wild-type EGFR in cellular assays measuring EGFR autophosphorylation and proliferation, suggesting an improved therapeutic index in non-small cell lung cancer patients would be achievable relative to established EGFR inhibitors. We describe our design approaches, resulting in the identification of the lead compound 5, and our efforts to develop an understanding of the structure-activity relationships within this series. In addition, strategies to overcome challenges around metabolic stability and aqueous solubility are discussed. Despite limitations in its physical properties, 5 is orally bioavailable in mice and demonstrates pronounced antitumor activity in in vivo models of mutant EGFR-driven cancers.
ABSTRACT
Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.
ABSTRACT
INTRODUCTION: The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins. AREAS COVERED: This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists. EXPERT OPINION: In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space - for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles - tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.
Subject(s)
Biomimetic Materials/pharmacology , Drug Design , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Animals , Apoptosis/drug effects , Humans , Molecular Targeted Therapy , Oligopeptides/chemistry , Patents as Topic , Signal Transduction/drug effectsABSTRACT
We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P1 receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits S1P-induced receptor internalization in a cell-based assay (EC50 = 0.05 µM), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P1 antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P1 antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P1 antagonists would have limited utility as anticancer therapeutics as single agents.
Subject(s)
Benzimidazoles/chemistry , Pyridines/chemistry , Receptors, Lysosphingolipid/antagonists & inhibitors , Sulfonamides/chemistry , Administration, Oral , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Biological Availability , Cells, Cultured , Cytochrome P-450 CYP3A/biosynthesis , Cytochrome P-450 CYP3A Inducers/chemical synthesis , Cytochrome P-450 CYP3A Inducers/chemistry , Cytochrome P-450 CYP3A Inducers/pharmacology , Genes, Reporter , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Models, Molecular , Molecular Structure , Pregnane X Receptor , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Steroid/genetics , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
[reaction: see text] A general method for the synthesis of alpha-aryl malonates is described. The coupling of an aryl iodide and diethyl malonate in the presence of Cs(2)CO(3) and catalytic amounts of copper(I) iodide and 2-phenylphenol affords the alpha-aryl malonate in good to excellent yields. The mild reaction conditions and high levels of functional group compatibility make this an attractive synthetic alternative to previous methods.
Subject(s)
Hydrocarbons, Aromatic/chemistry , Malonates/chemistry , Catalysis , Copper/chemistry , Hydrocarbons, Iodinated/chemistryABSTRACT
KIFC1 (HSET), a member of the kinesin-14 family of motor proteins, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division. To explore the potential of KIFC1 as a therapeutic target for human cancers, a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold was developed from hits identified through high-throughput screening (HTS). Optimization of the initial hits combined both design-synthesis-test cycles and an integrated high-throughput synthesis and biochemical screening method. An important aspect of this integrated method was the utilization of DMSO stock solutions of compounds registered in the corporate compound collection as synthetic reactants. Using this method, over 1500 compounds selected for structural diversity were quickly assembled in assay-ready 384-well plates and were directly tested after the necessary dilutions. Our efforts led to the discovery of a potent KIFC1 inhibitor, AZ82, which demonstrated the desired centrosome declustering mode of action in cell studies.
Subject(s)
Alanine/analogs & derivatives , Kinesins/antagonists & inhibitors , Pyridines/chemical synthesis , Alanine/chemical synthesis , Alanine/pharmacology , Animals , HeLa Cells , High-Throughput Screening Assays/methods , Humans , Inhibitory Concentration 50 , Mice , Phenylalanine/analogs & derivatives , Pyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.
Subject(s)
Alkynes/pharmacology , Antineoplastic Agents/pharmacology , Biomimetic Materials/pharmacology , Drug Discovery , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Oligopeptides/pharmacology , Alkynes/chemical synthesis , Alkynes/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dimerization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Inhibitor of Apoptosis Proteins/metabolism , Mice , Molecular Conformation , Neoplasms/pathology , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
DAPH (4,5-dianilinophthalimide) has previously been shown to reverse the formation of neurotoxic fibrils associated with Alzheimer's disease. We have developed a synthetic route to DAPH and structurally related analogues that employs palladium-catalyzed amination as the key bond-forming step. The requisite substrates are easily obtained, and their coupling with substituted anilines proceeds in generally high yields. Thus, a variety of DAPH analogues can be quickly accessed in a modular fashion. In addition, the route described herein should also be amenable to the incorporation of other classes of nucleophiles into the molecular framework.
Subject(s)
Alzheimer Disease/drug therapy , Palladium/chemistry , Phthalimides/chemical synthesis , Amination , CatalysisABSTRACT
A novel method for the synthesis of oxindoles is described. In the presence of catalytic palladium acetate and 2-(di-tert-butylphosphino)biphenyl, alpha-chloroacetanilides are converted to oxindoles in good to excellent yields with high functional group compatibility using triethylamine as a stoichiometric base. The cyclization is highly regioselective, obviating the need for prefunctionalized arenes. Plausible mechanistic pathways for the reaction are discussed.