The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.

ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

Insight into the mechanism of hydrogenation of amino acids to amino alcohols catalyzed by a heterogeneous MoO(x) -modified Rh catalyst.

Hydrogenation of amino acids to amino alcohols is a promising utilization of natural amino acids. We found that MoOx -modified Rh/SiO2 (Rh-MoOx /SiO2 ) is an efficient heterogeneous catalyst for the reaction at low temperature (323 K) and the addition of a small amount of MoOx drastically increases the activity and selectivity. Here, we report the catalytic potential of Rh-MoOx /SiO2 and the results of kinetic and spectroscopic studies to elucidate the reaction mechanism of Rh-MoOx /SiO2 catalyzed hydrogenation of amino acids to amino alcohols. Rh-MoOx /SiO2 is superior to previously reported catalysts in terms of activity and substrate scope. This reaction proceeds by direct formation of an aldehyde intermediate from the carboxylic acid moiety, which is different from the reported reaction mechanism. This mechanism can be attributed to the reactive hydride species and substrate adsorption caused by MoOx modification of Rh metal, which results in high activity, selectivity, and enantioselectivity.

Selective hydrogenation of lactic acid to 1,2-propanediol over highly active ruthenium-molybdenum oxide catalysts.

Modification of Ru/C with a small amount of MoOx (RuMoOx /C) enhanced the catalytic activity in the hydrogenation of L-lactic acid to form 1,2-propanediol and maintained high selectivity. The turnover frequency based on the amount of Ru over the optimized RuMoOx /C catalyst (Mo/Ru molar ratio=1:16) was 114 h(-1) at 393 K, which was about 4 times higher than that over Ru/C. The same effect of MoOx was obtained over RuMoOx /SiO2 , although RuMoOx /SiO2 showed slightly lower activity than that of RuMoOx /C. RuMoOx /C achieved a high yield of 95 % in 18 h at 393 K and was applicable to various carboxylic acids to provide the corresponding alcohols in high yields. Modification with MoOx also brought about suppression of racemization and (S)-1,2-propanediol was obtained in high enantiomeric excess at 353 K. Based on kinetic analysis and characterization data, such as XRD, TEM, CO adsorption by a volumetric method, FTIR spectroscopy, and X-ray absorption spectroscopy, for RuMoOx /C and RuMoOx /SiO2 , the catalyst structure and reaction mechanism are proposed.

Catalytic hydrogenation of amino acids to amino alcohols with complete retention of configuration.

Rh-MoOx/SiO2 is an effective heterogeneous catalyst for selective hydrogenation of amino acids to amino alcohols in a water solvent. MoOx modification of Rh drastically enhanced the activity and improved the selectivity and ee. Various amino alcohols were obtained in high yields (90-94%) with complete retention of configuration.

Distribution of antimicrobial-resistant lactic acid bacteria in natural cheese in Japan.

To determine and compare the extent of contamination caused by antimicrobial-resistant lactic acid bacteria (LAB) in imported and domestic natural cheeses on the Japanese market, LAB were isolated using deMan, Rogosa and Sharpe (MRS) agar and MRS agar supplemented with six antimicrobials. From 38 imported and 24 Japanese cheeses, 409 LAB isolates were obtained and their antimicrobial resistance was tested. The percentage of LAB resistant to dihydrostreptomycin, erythromycin, and/or oxytetracycline isolated from imported cheeses (42.1%) was significantly higher than that of LAB resistant to dihydrostreptomycin or oxytetracycline from cheeses produced in Japan (16.7%; P=0.04). Antimicrobial resistance genes were detected in Enterococcus faecalis (tetL, tetM, and ermB; tetL and ermB; tetM) E. faecium (tetM), Lactococcus lactis (tetS), Lactobacillus (Lb.), casei/paracasei (tetM or tetW), and Lb. rhamnosus (ermB) isolated from seven imported cheeses. Moreover, these E. faecalis isolates were able to transfer antimicrobial resistance gene(s). Although antimicrobial resistance genes were not detected in any LAB isolates from Japanese cheeses, Lb. casei/paracasei and Lb. coryniformis isolates from a Japanese farm-made cheese were resistant to oxytetracycline (minimal inhibitory concentration [MIC], 32 µg/mL). Leuconostoc isolates from three Japanese farm-made cheeses were also resistant to dihydrostreptomycin (MIC, 32 to >512 µg/mL). In conclusion, the present study demonstrated contamination with antimicrobial-resistant LAB in imported and Japanese farm-made cheeses on the Japanese market, but not in Japanese commercial cheeses.

Mechanisms and rules of anion partition into ionic liquids: phenolate ions in ionic liquid/water biphasic systems.

It is important to understand the mechanisms and general rules of ion partitioning in hydrophobic ionic liquid (IL)/water biphasic systems in order to predict the extractability of an ionic species with various ILs. In this study, we have investigated the partition of picrate ion (target anion, T(-)) from aqueous sodium picrate solutions into several ILs and the accompanying changes in aqueous concentrations of the IL component cation (C(+)) and anion (A(-)) at 298.2 K. The main ILs examined are 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide, 1-butyl-3-methylimidazolium hexafluorophosphate, and 1-methyl-3-octylimidazolium bis(trifluoromethanesulfonyl)amide. The aqueous concentrations of C(+) and A(-) decreased and increased, respectively, with the extraction of T(-) into the IL phase. From the standpoint of equilibrium, the partition behavior of T(-) can be explained both by the anion exchange with A(-) in the IL phase and by the ion pair extraction with C(+) in the aqueous phase. The aqueous concentrations of C(+) and A(-) are governed by the solubility product of the IL (K(sp)). The distribution ratio of T(-) is expressed as a function of Δ[T(-)](W), namely, the difference between the initial and equilibrium concentrations of T(-) in the aqueous phase; the distribution ratio of T(-) is nearly constant when Δ[T(-)](W) << K(sp)(1/2), but decreases with increasing Δ[T(-)](W) in the larger Δ[T(-)](W) region. The equilibrium constants of the ion pair extraction and the ion exchange extraction have been determined for picrate and other phenolate ions whose partition data were previously reported. The dependences of the extraction constants and extractability on the kinds of IL component ions can be quantitatively explained on the basis of the variations of K(sp).

Ion-pair formation between Cd(II), Na(I), and Ag(I) complex ions with 18-crown-6 ether derivatives and various pairing anions in water: an understanding of the ion-pair formation based on the HSAB principle.

The ion-pair formation constants (K(MLX)(0)/mol(-1) dm(3)) of CdL(2+) with Br(-) or NaL(+) with N,N-diethyldithiocarbamate ion (DDTC(-)) in water were determined potentiometrically at 25°C; ionic strength (I)→0: L denotes 18-crown-6 ether (18C6) and its mono-benzo derivative for the CdBr(2)-L system and 15-crown-5 ether and 18C6 for the NaDDTC-L one. The formation constant corresponding to the simple salt, NaDDTC, in water was also determined at I→0. Using the log K(CdLX)(0) values of CdLCl(+), CdLBr(+), CdLPic(+), and CdLSO(4), then CdL(2+) and picrate ion (Pic(-)) in water have been classified with the hard and soft acids and bases principle, where the values were available in the literature, except for CdLBr(+). The same classification was examined in NaX-L systems with X(-) = DDTC(-), trifluoroacetate ion, MnO(4)(-), ReO(4)(-), Pic(-), and BPh(4)(-) and the AgPic-L one. Consequently, CdL(2+), NaL(+), and AgL(+) were classified as the hard acids, while Pic(-) and BPh(4)(-) as the hard bases. These results reflected the reactivities of the complex ions in ion-pair formation with X(-) and SO(4)(2-) in water.

Extraction of some univalent salts into 1,2-dichloroethane and nitrobenzene: analysis of overall extraction equilibrium based on elucidating ion-pair formation and evaluation of standard potentials for ion transfers at the interfaces between their diluents and water.

Sodium permanganate, sodium picrate (NaPic), Bu(4)NPic, Me(4)NPic, and Et(4)NPic were extracted at an ionic strength of 2 × 10(-5) to 0.08 mol dm(-3) and 25°C from water (w)-phases into the organic (o)-ones, 1,2-dichloroethane (DCE) and nitrobenzene (NB). Thereby, apparent distribution constants (K(D,±)) of the anions (A(-)) or the cations (M(+)) and ion-pair formation ones (K(MA)(org)) of the univalent salts (MA) in the o-phases were determined at 25 °C, where K(D,±) = ([A(-)](o)[M(+)](o)/[A(-)][M(+)])(1/2) = (K(D,A)K(D,M))(1/2) and K(MA)(org) = [MA](o)/[M(+)](o)[A(-)](o). Also, the K(ex) and K(D,MA) values with A(-) = Pic(-), MnO(4)(-) were estimated from the relations K(ex) (= [MA](o)/[M(+)][A(-)]) = K(MA)(org)(K(D,±))(2) and = K(MA)K(D,MA), respectively. Standard potentials (Δψ(tr)(0)) for ion transfers at the w/DCE and w/NB interfaces were evaluated from the log K(D,A) or log K(D,M) values by assuming the relations K(D,Pic) = K(D,Et4N) and = K(D,Me4N), respectively. The thus-obtained Δψ(tr)(0) values, especially for the w/DCE system, were in good agreement with the values based on the extra-thermodynamic assumption for Ph(4)As(+) and BPh(4)(-) transfers at the interfaces. In the present extraction systems, the ion-pair formation of MA in the w- and o-phases was less effective in the determination of their distribution constants into the two o-phases.

Discovery of novel Thieno[2,3-d]pyrimidin-4-yl hydrazone-based cyclin-dependent kinase 4 inhibitors: synthesis, biological evaluation and structure-activity relationships.

The design, synthesis, and evaluation of novel thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as cyclin-dependent kinase 4 (CDK4) inhibitors are described. In continuing our program aim to search for potent CDK4 inhibitors, the introduction of a thiazole group at the hydrazone part has led to marked enhancement of chemical stability. Furthermore, by focusing on the optimization at the C-4' position of the thiazole ring and the C-6 position of the thieno[2,3-d]pyrimidine moiety, compound 35 has been identified with efficacy in a xenograft model of HCT116 cells. In this paper, the potency, selectivity profile, and structure-activity relationships of our synthetic compounds are discussed.

Evaluation of the hydrophilic properties of crown ether-ion-pair complexes with alkali metal picrates by their distribution into less-polar diluents.

Cohesive energy densities (C(w,MLA)/J cm(-3)) for ion-pair complexes (MLA: M(+) = Li(+) to Cs+; w: water) with six crown ethers (L), such as 18-crown-6 ether (18C6), benzo-18C6, and dibenzo-24-crown-8 one, and A(-) = picrate were calculated at 298 K by a procedure that uses either (i) an equation rearranged from that underlying log K(D,MLA)-vs.-log K(D,L) plots or (ii) intercepts of their plots and from both procedures. Here, K(D,MLA) and K(D,L) denote the distribution constants of MLA and L from w into a diluent, respectively. As additional MLA, Na(18C6)(2,4-dinitrophenolate) and Na(18C6)(2,6-dinitrophenolate) were employed for the present C(w,MLA) calculation. The C(w,MLA) values calculated from the two procedures agreed well, and they were proportional to the log(K(D,MLA))(-1) values. From the log K(D,MLA) values for dinitrophenolates and previously-reported values for Na(18C6)A, the hydrophobic property of some pairing anions, A(-), was ordered as F(3)CCO(2)(-) < ReO(4)(-) < MnO(4)(-) < 2,4-dinitrophenolate < 2,6-dinitrophenolate < picrate, and then discussed based on a relation with the log K(ex) values, where K(ex) shows the extraction constant (mol(-2) dm(6) unit) for Na(18C6)A into 1,2-dichloroethane.

Selective extraction of lithium with a macrocyclic trinuclear complex of (1,3,5-trimethylbenzene)ruthenium(II) bridged by 2,3-dioxopyridine.

A macrocyclic trinuclear complex of (1,3,5-trimethylbenzene)ruthenium(II) bridged by 2,3-dioxopyridine was synthesized, and the extraction properties for lithium and sodium picrates were investigated in a dichloromethane/water system at 25 degrees C. The complex was found to have extremely high extractability and selectivity for lithium picrate; the logarithmic values of the extraction constants are 5.86 and 2.63 for Li(+) and Na(+), respectively. By using this complex as an extractant, nearly quantitative extraction and separation of Li(+) from Na(+) could be achieved by a single extraction.

Distribution of 1-alkyl-3-methylimidazolium ions and their ion pairs between dichloromethane and water.

The distribution behavior of the salts of a series of 1-alkyl-3-methylimidazolium cations (RMeIm(+); R = butyl, hexyl, and octyl) with tetrafluoroborate (BF(4)(-)), hexafluorophosphate (PF(6)(-)), bis(trifluoromethanesulfonyl)amide (NTf(2)(-)), and 2,4,6-trinitrophenolate (Pic(-)) anions has been investigated in a dichloromethane-water system at 25 degrees C. The distribution constants (K(D)) of the ion pairs and the transfer activity coefficients ((o)gamma(w)) of the single ions were determined. For the ion pairs with a given anion, the log K(D) value increases linearly with the number of methylene groups (N(CH2)) in the cation, which can be explained by using the regular solution theory. A similar relationship was observed between log (o)gamma(w) and N(CH2) for the free RMeIm(+) ions, and the result was discussed by decomposing the transfer activity coefficient into the Born-type electrostatic contribution and the non-electrostatic one. For the free anions and their ion pairs with a given cation, the (o)gamma(w) and K(D) values increase with increasing molar volume of the anion: i.e., BF(4)(-) < PF(6)(-) < Pic(-) < NTf(2)(-). The features of the RMeIm(+) salts in the liquid-liquid distribution and the ion-pair formation in water are also discussed by comparing the present results with those of tetraalkylammonium salts previously reported.

Evaluation of the hydrophilic property of sodium ion-pair complexes with 3m-crown-m ethers (m = 5, 6) and their benzo-derivatives by solvent extraction.

The ion-pair formation constants {K(j)(0): j = MA (metal salt), MLA} of NaO(2)CCF(3) (Na(+)tfa(-)) and its ion-pair complexes (MLA) in water (w) were determined potentiometrically at 25 degrees C and an ionic strength (I) of zero. 15-Crown-5 (15C5), 18-crown-6 ethers (18C6), and their mono-benzo derivatives were used as crown ethers (L). The extraction of Natfa by these four L from w into 1,2-dichloroethane was done at 25 degrees C, and then the extraction constants (K(ex)) for NaLtfa were calculated by using the K(j) values, which were estimated from the corresponding K(j)(0) ones at I of the w-phases, and other equilibrium constants. Also, the distribution constants (K(D,MLA)) of NaLtfa between the two phases were obtained from a thermodynamic cycle expressing K(ex). An interaction of w-molecules with NaLA was considered using a relation of log K(D,MLA) with log K(D,L), derived from the Scatchard-Hildebrand equation, where K(D,L) denotes the distribution constant of L between the two phases. The interaction increased in the order of NaL (picrate) < free L

Hydration effect on the ion-pair extraction of lithium picrate by hydrophobic benzo-15-crown-5 ether into various less-polar diluents.

The ion-pair formation constant (K(MLA)(0) in mol(-1) dm(3)) for Li(B15C5)(+) with a picrate ion (Pic(-)) in water was determined by potentiometry with a K(+)-selective electrode at 25 degrees C and an ionic strength of 0, where B15C5 denotes benzo-15-crown-5 ether. Using the concentration equilibrium constants, K(MLA), estimated from this value, the extraction constants (mol(-2) dm(6) unit) of about ten diluents were re-calculated from previously reported extraction data. Also, the distribution constants of an ion-pair complex, Li(B15C5)Pic, between water and the diluents were re-estimated. A disagreement in the determined K(MLA) value between a solvent-extraction method and potentiometry was explained in terms of the Scatchard-Hildebrand equation; it came from the fact that the hydration of Li(I) in Li(B15C5)Pic was larger than that of free B15C5 in water. Then, the previously determined value by the former method was re-estimated using the potentiometric K(MLA) value.

Solvent extraction of sodium perrhenate by 3m-crown-m ethers (m=5, 6) and their mono-benzo-derivatives into 1,2-dichloroethane: Elucidation of an overall extraction equilibrium based on component equilibria containing an ion-pair formation in water.

Equilibrium constants (K(MLA)(0)/mol(-1)dm(3)) for the ion-pair formation of a complex ion NaL(+) with ReO(4)(-) in water were determined potentiometrically at 25 degrees C and the ionic strength (I) of 0mol dm(-3) using a Na(+)-selective electrode. Here, crown ethers, L, were 15-crown-5 ether (15C5), benzo-15C5, 18-crown-6 ether (18C6) and benzo-18C6. Also, NaReO(4) was extracted by the L into 1,2-dichloroethane and then extraction constants (K(ex)/mol(-2)dm(6)) for the species, NaLReO(4), were determined at 25 degrees C by AAS. These K(ex) values were resolved into four component equilibrium constants containing K(MLA) calculated at given I values. Based on these data, extraction-abilities of the L against the perrhenate were discussed in comparison with those of sodium picrate-L systems reported previously.

Determination of ion-pair formation constants of univalent metal-crown ether complex ions with anions in water using ion-selective electrodes: application of modified determination methods to several salts.

Ion-pair formation constants (mol(-1) dm3 unit), K(MX) for a univalent metal salt (MX) and K(MLX) for its ion-pair complex (ML+X-) with a crown ether (L) in water, were determined at various ionic strengths (I) and 25 degrees C by potentiometry with ion-selective electrodes for MX=NaPic, NaMnO4, NaBPh4, KPic, and KMnO4; and MLX = Na(18C6)Pic, K(18C6)Pic, and Na(18C6)BPh4, where Pic- and 18C6 denote a picrate ion and 18-crown-6 ether, respectively. Equations for analyzing I-dependence of logK(MLX) and logK(MX) were derived and fitted well to the I-dependence using a non-linear regression analysis. The equilibrium constants at I = 0 mol dm(-3), K(MLX) degrees and K(MX) degrees, were simultaneously obtained from the analysis. The experimental values of K(MLX) and K(MX) were only in agreement with the values calculated from K(MLX) degrees and K(MX) degrees , respectively, in the ranges of higher I.

New highly active taxoids from 9 beta-dihydrobaccatin-9,10-acetals. Part 5.

To improve the metabolic stability of 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, we designed and synthesized new taxane analogues. Most of the synthetic compounds maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes. And some compounds exhibited potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration similarly to 3.

Solvent extraction of silver picrate by 3m-crown-m ethers (m = 5, 6) and its mono-benzo-derivative from water into benzene or chloroform: elucidation of an extraction equilibrium using component equilibrium constants.

Ion-pair formation constant (K(AgPic) in mol(-1)dm(3)) of silver picrate (AgPic), those (K(AgLPic)) of its ion-pair complexes (AgLPic) with crown ethers (L) and complex formation constants (K(AgL)) of Ag(+) with L (15-crown-5 ether (15C5) and benzo-15C5) in water (w) were determined potentiometrically at 25 degrees C. Compounds used as L were 18-crown-6 ether (18C6), its benzo-derivative (B18C6) and the two 15C5 derivatives. Extraction constants (K(ex) in mol(-1)dm(3)) of AgPic with L (15C5, 18C6, B18C6) from acidic w-phases into either C(6)H(6) or CHCl(3) were recalculated from K(AgPic), K(AgL), K(AgLPic) and data opened in previous papers. Thus obtained K(ex) was divided into five component equilibrium constants containing K(AgL) and K(AgLPic) anew. Then, contributions of the component constants, K(AgL), K(AgLPic) and distribution constants of AgLPic between the w- and C(6)H(6)-phases, to K(ex) were discussed and compared with corresponding extraction systems of NaPic and KPic with18C6.

New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 4.

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.

New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 3.

We synthesized novel water-soluble and orally active taxane analogues, 7-deoxy-9beta-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compounds were greater than those of paclitaxel and docetaxel, especially against resistant cancer cell lines expressing P-glycoprotein. In addition, some compounds showed potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration.