An unusual ionic cocrystal of ponatinib hydrochloride: characterization by single-crystal X-ray diffraction and ultra-high field NMR spectroscopy.

This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride (pon·HCl), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon·HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a "square" arrangement with three water molecules. Multinuclear SSNMR, featuring high and ultra-high fields up to 35.2 T, provides the groundwork for structural interpretation of complex multicomponent crystals in the absence of diffraction data. A 13C CP/MAS spectrum confirms the presence of two crystallographically distinct ponatinib molecules, whereas 1D 1H and 2D 1H-1H DQ-SQ spectra identify and assign the unusually deshielded imidazopyridazine proton. 1D 35Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, with density functional theory calculations providing key relationships between the SSNMR spectra and H⋯Cl- hydrogen bonding arrangements. A 2D 35Cl → 1H D-RINEPT spectrum confirms the spatial proximities between the chloride ions, water molecules, and amine moieties. This all suggests future application of multinuclear SSNMR at high and ultra-high fields to the study of complex API solid forms for which SCXRD data are unavailable, with potential application to heterogeneous mixtures or amorphous solid dispersions.

The geography of demography: long-term demographic studies and species distribution models reveal a species border limited by adaptation.

Potential causes of species' geographic distribution limits fall into two broad classes: (1) limited adaptation across spatially variable environments and (2) limited opportunities to colonize unoccupied areas. Combining demographic studies, analyses of demographic responses to environmental variation, and species distribution models, we investigated the causes of range limits in a model system, the eastern border of the California annual plant Clarkia xantiana ssp. xantiana. Vital rates of 20 populations varied with growing season temperature and precipitation: fruit number and overwinter survival of 1-year-old seeds declined steeply, while current-year seed germination increased modestly along west-to-east gradients in decreasing temperature, decreasing mean precipitation, and increasing variation in precipitation. Long-term stochastic finite rate of increase, λ(s), exhibited a fourfold range and varied among geologic surface materials as well as with temperature and precipitation. Growth rate declined significantly toward the eastern border, falling below 1 in three of the five easternmost populations. Distribution models employing demographically important environmental variables predicted low habitat favorability beyond the eastern border. Models that filtered or weighted population presences by λ(s) predicted steeper eastward declines in favorability and assigned greater roles in setting the distribution to among-year variation in precipitation and to geologic surface material. These analyses reveal a species border likely set by limited adaptation to declining environmental quality.

Pentacyclic furanosteroids: the synthesis of potential kinase inhibitors related to viridin and wortmannolone.

A regiocontrolled intermolecular Diels-Alder reaction of an o-benzoquinone followed by an intramolecular nitrile oxide cyclization is employed to prepare the BCD fragment of viridin. The AE segment is attached to it by means of an intramolecular Diels-Alder reaction of an o-benzoquinone monoketal generated in situ from tricycle 15 and 5-trimethylsilyl-2E,4E-pentadienol 20. The silyl substituent at C-1 of the pentacyclic product directs the dihydroxylation of the C2-C3 double bond to its beta-face. Various transformations of the 1alpha-trimethylsilyl-2beta,3beta-dihydroxy pentacycle into several others with oxygen substituents in ring A are described. One of these products 40 possesses the same structure and relative stereochemistry in rings A, B, and E as that of the natural product wortmannolone 3.

Drug resistance among chronic HIV-1-infected patients naïve for use of anti-retroviral therapy in Sao Paulo city.

Primary infection with drug-resistant HIV appears to be increasing in the regions where HAART is widely available, which may reduce efficacy of first-line antiretroviral therapy. To determine prevalence of antiretroviral drug-resistant mutations in newly diagnosed subjects in a clinical setting where HAART has been widely used since 1997. One hundred and thirty-six HIV-1-infected adult patients were diagnosed with HIV infection between January 2000 and December 2006 in the HIV out-clinic at the HC/FMUSP, Sao Paulo city. These antiretroviral naïve patients were mainly referred from the blood bank, situated in the same building or elsewhere in the city. The samples were genotyped to provide HIV protease and reverse transcriptase sequence data. Major antiretroviral drug resistance mutations were classified according to Shafer et al. [Shafer, R.W., Rhee, S.Y., Pillay, D., et al., 2007. HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS 21, 215-223]. Thirteen cases had no DNA amplification, and 123 patients were successfully analyzed, with a mean age of 37 years and 89 (72%) were males. Antiretroviral drug resistance mutations were detected in 8/123 patients (6.5%), all eight were heterosexuals and HIV asymptomatic, the mean of the CD4 cells count was 323 cells/mm(3), and the RNA plasma viral load was 4.7 log(10)/mL. We found NRTI (n=2, 1.6%), NNRTI-resistant (n=2, 1.6%) mutations, and one cases with PI mutation (0.8%). Three cases (2.4%) showed mutations for NRTI, NNRTI or PI, simultaneously. Eighty-two percent were HIV-1 B subtype, and HIV-1 F (6.5%), HIV-1 C (5.7%) and recombinant viruses (5.8%) were observed. In an unselected cohort, primary drug resistance was seen in 6.5% of the naïve for drug ART use. These results indicate that HIV drug resistance testing should be a practical approach in monitoring first-line ART. In addition, HIV-1 C seems to be emerging in Sao Paulo city.

(Z)-tamoxifen and tetrasubstituted alkenes and dienes via a regio- and stereospecific three-component magnesium carbometalation palladium(0) cross-coupling strategy.

[reaction: see text] The synthesis of various tetrasubstituted alkenes and dienes in a regio- and stereocontrolled manner is described. This three-component coupling strategy involves the addition of Grignard reagents to propargyl alcohols followed by palladium(0)-mediated cross-coupling with aryl or vinyl halides. This protocol has been applied to the synthesis of (Z)-Tamoxifen and related mimics.

Rhodium catalysed dehydrogenative borylation of vinylarenes and 1,1-disubstituted alkenes without sacrificial hydrogenation--a route to 1,1-disubstituted vinylboronates.

The complex trans-[Rh(Cl)(CO)(PPh3)2] (1) is an efficient catalyst precursor for the dehydrogenative borylation of alkenes without consumption of half the alkene substrate by hydrogenation, giving useful vinylboronate esters including 1,1-disubstituted derviatives that cannot be made by alkyne hydroboration.

Rhodium catalysed dehydrogenative borylation of alkenes: vinylboronates via C-H activation.

We present herein a high yield, highly selective catalytic synthesis of vinylboronate esters (VBEs), including 1,1-disubstituted VBEs, from alkenes without significant hydrogenation or hydroboration, using the simple catalyst precursor, trans-[RhCl(CO)(PPh3)2] (1), and the diboron reagents B2pin2 (2a, pin = pinacolato = OCMe2CMe2O) or B2neop2 (2b, neop = neopentylglycolato = OCH2CMe2CH2O), or the monoboron reagent HBpin, all of which are commercially available. The reactions were conducted at 80 degrees C using conventional heating, or in a microwave reactor at 150 degrees C.

A general carbometalation, three component coupling strategy for the synthesis of alpha,beta-unsaturated gamma-sultines including thio-rofecoxib, a selective COX-2 inhibitor.

Magnesium mediated carbometalation (Grignard addition) to appropriate propargyl alcohols to synthesize a cross-section of variably substituted alpha,beta-unsaturated gamma-sultines is described. Thio-rofecoxib, a selective COX-2 inhibitor (12), is synthesized by this method and its IC(50), microM COX-1 and COX-2 inhibition, and whole blood stability values reported.

A two-step conversion of alpha,beta-unsaturated ketones to their alpha-carbalkoxy or alpha-carbamoyl derivatives.

Several enones are converted into their alpha-iodo derivatives in excellent yields and carbonylated with palladium catalysis in the presence of alcohol or amines to the alpha-carbonyl enones in satisfactory yields.