Dissolving microneedles are especially attractive for transdermal drug delivery as they are associated with improved patient compliance and safety. Furthermore, microneedles made of sugars offer the added benefit of biomolecule stabilisation making them ideal candidates for delivering biological agents such as proteins, peptides and nucleic acids. In this study, we performed experimental and finite element analyses to study the mechanical properties of sugar microneedles and evaluate the effect of sugar composition on microneedle ability to penetrate and deliver drug to the skin. Results showed that microneedles made of carboxymethylcellulose/maltose are superior to those made of carboxymethylcellulose/trehalose and carboxymethylcellulose/sucrose in terms of mechanical strength and the ability to deliver drug. Buckling was predicted to be the main mode of microneedle failure and the order of buckling was positively correlated to the Young's modulus values of the sugar constituents of each microneedle.

Computerized tomography (CT scan) imaging and finite element analysis were employed to investigate how the geometric composition of microneedles affects their mechanical strength and penetration characteristics. Simulations of microneedle arrays, comprising triangular, square and hexagonal microneedle base, revealed a linear dependence of the mechanical strength to the number of vertices in the polygon base. A laser-enabled, micromoulding technique was then used to fabricate 3x3 microneedle arrays, each individual microneedle having triangular, square or hexagonal base geometries. Their penetration characteristics into ex-vivo porcine skin, were investigated for the first time by CT scan imaging. This revealed greater penetration depths for the triangular and square-based microneedles, demonstrating CT scan as a powerful and reliable technique for studying microneedle skin penetration.

Syntheses of the three key building blocks (65, 98, and 100) required for the total synthesis of the proposed structure of azaspiracid-1 (1a) are described. Key steps include a TMSOTf-induced ring-closing cascade to form the ABC rings of tetracycle 65, a neodymium-catalyzed internal aminal formation for the construction of intermediate 98, and a Nozaki-Hiyama-Kishi coupling to assemble the required carbon chain of fragment 100. The synthesized fragments, obtained stereoselectively in both their enantiomeric forms, were expected to allow for the construction of all four stereoisomers proposed as possible structures of azaspiracid-1 (1a-d), thus allowing the determination of both the relative and absolute stereochemistry of the natural product.

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In the preceding Communication in this issue [1] we described the total synthesis of a potential decalin precursor to azadirachtin (1), [2] its coupling to a suitable norbornene fragment 4 (Scheme 1), and the elaboration of the product to an advanced intermediate along the path to this synthetic target. Herein we report the total synthesis and semisynthesis from azadirachtin of a more advanced decalin system 3, its coupling to the same norbornene fragment 4, and the elaboration of the resulting product to an advanced intermediate for the total synthesis of azadirachtin (Scheme 1). This report also includes a number of unusual reactions induced by proximity effects and special steric factors highlighting the unique characteristics of the azadirachtin scaffold.Having successfully synthesized tricyclic decalin system 5, (Scheme 1) and explored its chemistry toward azadirachtin (1) as described in the preceding Communication, [1] we turned our attention to the more advanced tetracyclic decalin precursor 3, which bears the tetrahydrofuran ring system of 1 within its structure. Our plan to synthesize the targeted intermediate 3 required key building block 6 (Scheme 2) as

The extensive polymorphisms among HIV-1 subtypes have been implicated in drug resistance development. Integrase inhibitors represent the latest addition to the treatment of HIV-1, and their efficacy and resistance patterns among M group strains are currently under investigation. This study analyzed the intersubtype variation within 108 integrase sequences from seven subtypes. The residues associated with catalytic activity and primary resistance to raltegravir were highly conserved among all strains. Variations were observed in residues associated with secondary resistance. Molecular modeling studies indicated a two-way binding mode of raltegravir that explains the resistance pathways and the implication of nonconservative mutations in integrase-raltegravir interactions.

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