A convergent strategy for the stereoselective total synthesis of biologically active marine natural product biselyngbyolide B has been developed. Key strategies of this synthesis include Jamison protocol of trans-hydroalumination/allylation for installation of C18-C23 olefin moiety and intramolecular Heck coupling for macrocyclization.
Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with β-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys6)-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys6)LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys6)-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors α(v)β(3) and α(v)β(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.
A flexible and convergent strategy for the stereoselective total synthesis of bioactive marine natural product cytospolide Q has been developed. The key features of this synthesis include Evans anti-aldol reaction for the installation of C-2 and C-3 stereocenters and cycloetherification via epoxide opening followed by concomitant lactonization for the construction of tetrahydrofuran and γ-butyrolactone scaffolds. This synthetic study also revealed that protected oxygenated functionality (methyl ester or benzyl ether) at C-1 position participated readily in epoxide opening.
Chemically programmed bispecific antibodies (biAbs) endow target cell-binding small molecules with the ability to recruit and activate effector cells of the immune system. Here we report a platform of chemically programmed biAbs aimed at redirecting cytotoxic T cells to eliminate cancer cells. Two different antibody technologies were merged together to make a novel chemically programmed biAb. This was achieved by combining the humanized anti-hapten monoclonal antibody (mAb) h38C2 with the humanized anti-human CD3 mAb v9 in a clinically investigated diabody format known as Dual-Affinity Re-Targeting (DART). We show that h38C2 × v9 DARTs can readily be equipped with tumor-targeting hapten-derivatized small molecules without causing a systemic response harming healthy tissues. As a proof of concept, we chemically programmed h38C2 × v9 with hapten-folate and demonstrated its selectivity and potency against folate receptor 1 (FOLR1)-expressing ovarian cancer cells in vitro and in vivo Unlike conventional biAbs, chemically programmed biAbs in DART format are highly modular with broad utility in terms of both target and effector cell engagement. Most importantly, they provide tumor-targeting compounds access to the power of cancer immunotherapy.
Residual lateritic soils, developed in tropical and similar other climates associated with high temperature and abundant rainfall, are widely used as fill material for various construction activities. The effective use of these soils is often hindered by difficulty in handling them, particularly under moist and wet conditions typical of tropical regions. An attempt has been made to study the plasticity behaviour of a residually derived lateritic soil mixed with a low-calcium fly ash and lime. Three proportions of soil and fly ash were used, with the maximum amount of soil replaced with fly ash limited to 50%. Lime was added in quantities varying from 1% to 8% of the dry weight of soil or soil-fly ash mix. Atterberg limits were determined for the mixes after different curing periods up to 56 days. Owing to the presence of sesquioxides in the residual lateritic soil, unlike other soils, the addition of the low-calcium fly ash caused a decrease in the plastic limit.It was only when lime was also added that the plastic limit of the soil-fly ash mixes was noted to increase, leading to an improvement in workability. Les sols latéritiques résiduels, qui se développent dans des climats tropicaux et autres climats similaires à fortes températures et à précipitations abondantes sont largement utilisés comme matériaux de remblai lors de diverses activités de construction. L'utilisation efficace de ces sols est souvent gênée par un maniement difficile, plus particulièrement dans les conditions humides qui sont typiques des régions tropicales. Nous avons essayé d'étudier le comportement de plasticité d'un sol latéritique résiduel mélangé à de la cendre volante à faible teneur en calcium et à de la chaux. Nous avons utilisé trois proportions de sol et de cendre volante, le volume maximum de sol remplacé par de la cendre volante se limitant à 50%. De la chaux a été ajoutée en quantités représentant de 1 à 8% du poids sec du sol ou du mélange cendre-sol. Nous avons déterminé les limites d'Atterberg des mélanges apre's diverses périodes de durcissement allant jusqu'à 56 jours. En raison de la présence de sesquioxydes dans le sol latéritique résiduel, contrairement aux autres sols, l'adjonction de la cendre volante à faible teneur en calcium a causé une réduction de la limite plastique. Ce n'est que lorsque la chaux a été ajoutée que la limite plastique des mélanges cendre-sol a augmenté, provoquant une amélioration de la maniabilité.
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