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Aberrant activation of the HGF/MET pathway has frequently been found in human cancers via MET mutation, gene amplification and translocation, as well as HGF paracrine or autocrine upregulation. The abnormal HGF/MET signaling not only acts as an oncogenic driver but also confers resistance to many cancer therapies, such as EGFR targeted therapy in NSCLC. One key downstream effector for activated MET is SRC, which is also involved in malignancy formation, tumor metastasis and drug resistance. In the tumor microenvironment, CSF1R plays an important role in regulation of tumor associated macrophages, which promote tumor progression and angiogenesis. Therefore, the polypharmacological inhibition of MET/SRC/CSF1R has great potential for more effectively targeting cancers with abnormal HGF/MET signaling via targeting both tumor intrinsic signaling and the tumor microenvironment. TPX-0022, a novel macrocyclic compound, has been designed and optimized to inhibit MET/CSF1R/SRC with enzymatic kinase inhibition IC50s of 0.14, 0.76 and 0.12 nM, respectively. TPX-0022 potently inhibited cell proliferation of the MET-amplified MKN-45 and SNU-5 gastric cancer cells, with IC50s Citation Format: Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, Yuelie Lu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui. TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1321.

In the tumor microenvironment, tumor associated macrophages (TAMs) support tumor growth by suppressing antitumor immune responses and promoting angiogenesis, which is associated with disease progression and poor clinical outcomes. In contrast to the classic phagocytic and cytotoxic pro-inflammatory M1 phenotype of macrophages engulfing and digesting pathogens, TAMs often adopt the anti-inflammatory and immune regulatory M2 phenotype in response to colony stimulating factor 1 (CSF1), which is produced by either tumor cells or stroma cells. Signaling through colony stimulating factor 1 receptor (CSF1R), a receptor tyrosine kinase expressed on the surface of mononuclear phagocytes, is involved in the recruitment of TAMs and has been associated with tumor progression and suppression of the immune response. Thus, CSF1R represents a key therapeutic target. TPX-0022, a type I kinase inhibitor with a novel macrocyclic structure, has been designed and optimized to inhibit MET/CSF1R/SRC with enzymatic kinase inhibition IC50s of 0.14, 0.76 and 0.12 nM, respectively. In a Ba/F3 ETV6-CSF1R cell model, TPX-0022 inhibited both autophosphorylation of CSF1R with an IC50 Citation Format: Wei Deng, Dayong Zhai, Evan Rogers, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, Yuelie Lu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui. TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC inhibits tumor growth by promoting anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1325.

A practical and scalable synthesis of in vivo sphingosine-1-phosphate lyase inhibitor LX2931 (1) is described. The synthetic route features an improved Buchi cyclocondensation of 2-ethoxyacrylonitrile (3) with either 1-amino-1-deoxy-d-fructose acetate (4a) or d-(+)-glucosamine hydrochloride (4b) to produce 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone (2, THI), followed by oximation of THI and acid-promoted oxime isomerization to give LX2931 (1).

Synthesis of five and six membered heterocycles, indolines, 2,3-dihydrobenzofurans, chromans, isochromans, 1,2,3,4-tetrahydroquinolines, and 1,2,3,4-tetrahydroisoquinolines, in 70–99% yield by a ligand-free palladium catalyzed reductive Heck cyclization of phenyl bromides and chlorides, under mild conditions, is reported. Water was found to be essential for these reactions.

Novel αvβ3 antagonists based on the N-aryl-γ-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for αvβ3 receptor with excellent selectivity against the structurally related αIIbβ3 receptor. Additional interactions of N-aryl-γ-lactam derivatives with αvβ3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the γ-lactam core on the binding were also assessed.

Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3, 2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.

The piperidine catalyzed Knoevenagel condensation of 2′-aryl/alkyl-2-hydroxyacetophenones 7 and aryl/alkylaldehydes 8 in refluxing isopropyl alcohol with azeotropic removal of water affords, in high yield, equilibrium mixtures of E - and Z -chalcones 9 and cis - and trans -chroman-4-ones 10 which are effectively isomerized in situ to the trans -2,3-diaryl/alkylchroman-4-ones, following the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) to the cooled reaction mixture and may be isolated in high purities (91–99%) by simple filtration, with good to excellent yields (70–95%).

The piperidine catalyzed Knoevenagel condensation of 2′-aryl/alkyl-2-hydroxyacetophenones 7 and aryl/alkylaldehydes 8 in refluxing isopropyl alcohol with azeotropic removal of water affords, in high yield, equilibrium mixtures of E - and Z -chalcones 9 and cis - and trans -chroman-4-ones 10 which are effectively isomerized in situ to the trans -2,3-diaryl/alkylchroman-4-ones, following the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) to the cooled reaction mixture and may be isolated in high purities (91–99%) by simple filtration, with good to excellent yields (70–95%).

A method is described for measuring the overall quantum yields for free ions in the two-photon ionization of solutes in hydrocarbon liquids and for extracting the quantum yield for production of free ions from solute excited states. The zero electric field quantum yields at 308 nm and 25{degree}C for production of free ions from the singlet state of anthracene in n-hexane, cyclohexane, and isooctane (2,2,4-trimethylpentane) are 0.0023, 0.0058, and 0.017, respectively. Similarly, in isooctane, for the singlet states of fluoranthene, coronene, and TMPD (N,N,N{prime},N{prime}-tetramethyl-p-phenylenediamine), the quantum yields are 0.0039, 0.023, and 0.028, respectively. All of these quantum yields are for solutions saturated with SF{sub 6}{center dot}; in n-hexane and cyclohexane decreasing the concentration of SF{sub 6} by 2 orders of magnitude has no effect, but in isooctane the quantum yield of free ions increases by a factor of 2. The quantum yield results obtained with light of 308 nm are used in conjunction with measurements of the decay of conductivity due to the geminate ion pairs to obtain information on the distance distribution within the geminate pairs and the primary yield of photoionization. The analysis indicates that the primary quantum yields for ionization of the first excited singlet state ofmore » anthracene are approximately unit for isooctane and cyclohexane solutions, but may be as low as 0.4 for anthracene in n-hexane, and that an r{sup 2} Gaussian or f{sup 2} exponential distribution of separation distances explains the experimental observations better than an exponential distribution. Comparison with results obtained in radiolysis with electrons shows that the distribution of separation distances is narrower in the photochemical case, resulting in lower probability for separation into free ions.« less

Synthesis of five and six membered heterocycles, indolines, 2,3-dihydrobenzofurans, chromans, isochromans, 1,2,3,4-tetrahydroquinolines, and 1,2,3,4-tetrahydroisoquinolines, in 70–99% yield by a ligand-free palladium catalyzed reductive Heck cyclization of phenyl bromides and chlorides, under mild conditions, is reported. Water was found to be essential for these reactions.

Novel alphavbeta3 antagonists based on the N-aryl-gamma-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for alphavbeta3 receptor with excellent selectivity against the structurally related alpha(IIb)beta3 receptor. Additional interactions of N-aryl-gamma-lactam derivatives with alphavbeta3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the gamma-lactam core on the binding were also assessed.