ß-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis.

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert ß-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the ß-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester ß-carbons as nucleophiles (ß-carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic ß-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester ß-carbons to open a valuable new arena for new and useful reactions and synthetic strategies.

C-C bond formation via copper-catalyzed conjugate addition reactions to enones in water at room temperature.

Conjugate addition reactions to enones can now be done in water at room temperature with in situ generated organocopper reagents. Mixing an enone, zinc powder, TMEDA, and an alkyl halide in a micellar environemnt containing catalytic amounts of Cu(I), Ag(I), and Au(III) leads to 1,4-adducts in good isolated yields: no organometallic precursor need be formed.

Manipulating micellar environments for enhancing transition metal-catalyzed cross-couplings in water at room temperature.

The remarkable effects of added salts on the properties of aqueous micelles derived from the amphiphile PTS are described. Most notably, Heck reactions run in the presence of NaCl lead to couplings on aryl bromides in water at room temperature. Olefin cross- and ring-closing metathesis reactions run in the presence of small amounts of pH-lowering KHSO(4) are also accelerated, another phenomenon that does not apply to typical processes in organic media. These salt effects allow, in general, for synthetically valuable C-C bond-forming processes to be conducted under environmentally benign conditions. Recycling of the surfactant is also demonstrated.

Catalytic asymmetric formal [4 + 1] annulation leading to optically active cis-isoxazoline N-oxides.

The catalytic asymmetric synthesis of densely functionalized cis-isoxazoline N-oxides was realized with novel use of an organocatalyst, (S)-2-(azidodiphenylmethyl)pyrrolidine (4e) (Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem.-Eur. J. 2010, 16, 3842; Olivares-Romero, J. L.; Juaristi, E. Tetrahedron 2008, 64, 9992), via an elegant formal [4 + 1] annulation strategy using readily available 2-nitroacrylates and α-iodoaldehydes.

Deprotection of homoallyl ((h)Allyl) derivatives of phenols, alcohols, acids, and amines.

The homoallyl moiety, (h)Allyl, is presented as a general protecting group for several functionalities. It can be chemoselectively removed via a sequential, one-pot cross-metathesis/elimination sequence.

Expedient solid-phase synthesis of both symmetric and asymmetric diol libraries targeting aspartic proteases.

C(2)-symmetric diols have been shown to be highly potent against HIV-1 protease (PR). However, gaining access to these compounds has been hampered by the need of multistep solution-phase reactions which are often tedious and inefficient. In this Letter, we have disclosed a solid-phase strategy for rapid preparation of small molecule-based, symmetric and asymmetric diols as potential HIV-1 protease inhibitors. Upon biological screening, we found one of them, SYM-5, to be a potent and selective inhibitor (K(i)=400 nM) against HIV-1 protease.

Biopharmaceutics of 13-cis-retinoic acid (isotretinoin) formulated with modified beta-cyclodextrins.

13-cis-Retinoic acid (13-cis-RA), also known as isotretinoin, is commonly used in the management of severe acne. Its clinical efficacy in oncology has also been documented. As a vitamin A derivative, it is not soluble in water. This solubility barrier not only affects its oral absorption but also makes parenteral delivery difficult. Recently, water-soluble formulations of 13-cis-RA have been attempted with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-CD). In this study, the pharmacokinetic profiles of these two formulations were assessed in Sprague-Dawley rats after single intravenous or oral administration. We found that 13-cis-RA was eliminated from the body through a dose-independent process after intravenous injection of either sodium salt or the HP-beta-CD formulation within the tested dosage range (2.0-7.5mg/kg). Furthermore, HP-beta-CD did not alter the kinetic profile of 13-cis-RA after intravenous administration in comparison with 13-cis-RA sodium salt. We also found that RM-beta-CD dramatically enhanced the oral absorption of 13-cis-RA. At 10.0mg/kg, the bioavailability of 13-cis-RA formulated with RM-beta-CD was about three-fold higher than that of the control (13-cis-RA suspended in 0.5% carboxymethylcellulose (CMC)). Similarly, the oral absorption of 13-cis-RA was not saturated within our tested range (2.5-10.0mg/kg) and the bioavailability remained unchanged. These results demonstrated that HP-beta-CD and RM-beta-CD were suitable excipients for the delivery of 13-cis-RA.

Development of generic low molecular weight heparins: a perspective.

It is clear that the introduction of generic versions of low molecular weight heparins (LMWHs) is inevitable; however, it is important that the generic products are manufactured in strict compliance with the manufacturing specification of the branded product. Furthermore, regulatory agencies should require additional data on the chemical biologic, pharmacologic/toxicologic, and dose-response relationship in specific settings. Although there is strong opposition to stop the introduction of these drugs, their development will reduce cost and permit availability to all patients who need them. Some objective guidelines for the proper development of these drugs are needed. Only expert groups and advisory panels to the regulatory bodies can develop these guidelines.

Generic low-molecular-weight heparins: some practical considerations.

It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.

Generic forms of low-molecular-weight heparins: some practical considerations.

This commentary briefly reviews the controversies of therapeutic and generic interchangeability, as they apply to the antithrombotic drug class called low-molecular-weight heparin (LMWH). Recommendations are prepared for the generic LMWH approval process by various regulatory bodies.

Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients.

Regeneration of hematopoiesis after allogeneic hematopoietic cell transplantation (HCT) involves conversion of the recipient's immune system to donor type. It is likely that distinct cell lineages in the recipient reconstitute at different rates. Dendritic cells (DCs) are a subset of hematopoietic cells that function as a critical component of antigen-specific immune responses because they modulate T-cell activation, as well as induction of tolerance. Mature DCs are transferred with hematopoietic grafts and subsequently arise de novo. Little information exists about engraftment kinetics and turnover of this cell population in patients after allogeneic HCT. This study examined the kinetics of DC chimerism in patients who underwent matched sibling allogeneic HCT. T-cell, B-cell, and myelocytic and monocytic chimerism were also studied. Peripheral blood cells were analyzed at defined intervals after transplantation from 19 patients with various hematologic malignancies after treatment with myeloablative or nonmyeloablative preparatory regimens. Cell subsets were isolated before analysis of chimerism. Despite the heterogeneity of the patient population and preparatory regimens, all showed rapid and consistent development of DC chimerism. By day +14 after transplantation approximately 80% of DCs were of donor origin with steady increase to more than 95% by day +56. Earlier time points were examined in a subgroup of patients who had undergone nonmyeloablative conditioning and transplantation. These data suggest that a major proportion of blood DCs early after transplantation is donor-derived and that donor chimerism develops rapidly. This information has potential implications for manipulation of immune responses after allogeneic HCT.