Targeting hepatic cancer cells with pegylated dendrimers displaying N-acetylgalactosamine and SP94 peptide ligands.

Poly(amidoamine) (PAMAM) dendrimers are branched water-soluble polymers defined by consecutive generation numbers (Gn) indicating a parallel increase in size, molecular weight, and number of surface groups available for conjugation of bioactive agents. In this article, we compare the biodistribution of N-acetylgalactosamine (NAcGal)-targeted [(14) C]1 -G5-(NH2 )5 -(Ac)108 -(NAcGal)14 particles to non-targeted [(14) C]1 -G5-(NH2 )127 and PEGylated [(14) C]1 -G5-(NH2 )44 -(Ac)73 -(PEG)10 particles in a mouse hepatic cancer model. Results show that both NAcGal-targeted and non-targeted particles are rapidly cleared from the systemic circulation with high distribution to the liver.

Enzyme-activated nanoconjugates for tunable release of doxorubicin in hepatic cancer cells.

We report the synthesis of a series of aromatic azo-linkers (L1-L4), which are selectively recognized and cleaved by azoreductase enzymes present in the cytoplasm of hepatic cancer cells via a NADPH-dependent mechanism. We utilized L1-L4 azo-linkers to conjugate doxorubicin to generation 5 (G5) of poly(amidoamine) dendrimers to prepare G5-L(x)-DOX nanoconjugates. We incorporated electron-donating oxygen (O) or nitrogen (N) groups in the para and ortho positions of L1-L4 azo-linkers to control the electronegativity of G5-L(x)-DOX conjugates and investigated their cleavage by azoreductase enzymes and the associated release of loaded DOX molecules.

N-acetylgalactosamine-functionalized dendrimers as hepatic cancer cell-targeted carriers.

There is an urgent need for novel polymeric carriers that can selectively deliver a large dose of chemotherapeutic agents into hepatic cancer cells to achieve high therapeutic activity with minimal systemic side effects. PAMAM dendrimers are characterized by a unique branching architecture and a large number of chemical surface groups suitable for coupling of chemotherapeutic agents. In this article, we report the coupling of N-acetylgalactosamine (NAcGal) to generation 5 (G5) of poly(amidoamine) (PAMAM-NH₂) dendrimers via peptide and thiourea linkages to prepare NAcGal-targeted carriers used for targeted delivery of chemotherapeutic agents into hepatic cancer cells.

Total syntheses of isodomoic acids G and H: an exercise in tetrasubstituted alkene synthesis.

A unified approach to the pyrrolidine triacid natural products isodomoic acids G and H has been developed. Total syntheses of both natural products were completed, and determination of the correct stereostructure of isodomoic acid G was established by comparing 5'-(R) and 5'-(S) isomers to a sample of authentic material. A nickel-catalyzed cyclization constructs the pyrrolidine ring while simultaneously establishing either the E or Z stereochemistry of an exocyclic tetrasubstituted alkene.

Nickel and Palladium Catalysis in the Stereoselective Synthesis of Functionalized Pyrrolidines: Enantioselective Formal Synthesis of (+)-α-Allokainic Acid.

Neuroexcitatory natural products are accessible from 1 via the intermediate 2, which is obtained by Ni-catalyzed cyclization, transposition of the protecting group, and Pd-catalyzed reduction with allylic transposition. This stepwise formation of stereocenters allows a highly direct and stereoselective synthesis of the excitatory amino acid (+)-α-allokainic acid, which displays an all-trans arrangement of the substituents about the pyrrolidine ring. TBS=tert-butyldimethylsilyl.