Amy J. Pfizenmayer

Synthesis and biological activity of [Tic5] didemnin B

A didemnin B analog containing a Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) as a conformationally restrained replacement for tyrosine has been synthesized and shown to have comparable potency as a protein biosynthesis inhibitor. Synthetic highlights include an oxidation of an alcohol to an acid in the presence of the sensitive Tic heterocycle and a modified Schmidt-type one-pot macrocyclization.

Synthesis and biological activities of [N-MeLeu5]- and [N-MePhe5]-didemnin B

Abstract Based on information from X-ray, NMR, and SAR data, the N , O -diMeTyr 5 unit of didemnin B was believed to be important for biological activity. To determine the importance of aromaticity and the role of the methoxy group in this unit, two analogs were synthesized in which the N , O -diMeTyr 5 moiety was replaced with N -MeLeu and N -MePhe. Preliminary testing showed that the analogs retained antitumor activity and the ability to inhibit protein biosynthesis in vitro .

[Lys3]Didemnins as potential affinity ligands.

The synthesis and biological activity of N(epsilon)-Z-[Lys3]didemnin B are reported. This novel analogue retains antiproliferative, cytotoxic, and protein biosynthesis inhibition activities, but at reduced levels. This result suggests the use of [Lys3]didemnin derivatives as potential affinity probes for studying the molecular target(s) of the didemnin class of natural products.

Synthesis and biological activities of [N-MeLeu5] didemnin B

Abstract Based on information from X-ray, NMR, and SAR data, the N,O-diMeTyr5 unit of didemnim B was believed to interact with receptors. To ascertain the importance of this unit, an analog was synthesized in which the N,O-diMeTyr5 moiety was replaced with N-McLeu. Preliminary biological testing showed that the analog retained antitumor activity and the ability to inhibit protein biosynthesis.

Synthetic studies of a constrained ring didemnin analog

Abstract An asymmetric Diels-Alder reaction in the presence of 3.0 M lithium perchlorate-diethyl ether was used to generate the initial stereochemistry for a cyclohexane amino acid ( 3 ), a key intermediate in the preparation of a fused ring didemnin analog. This constrained ring macrocycle should provide insight into the binding site conformation of the bioactive species.

Synthesis and biological evaluation of didemnin photoaffinity analogues

The synthesis of four benzophenone-containing analogues of the antiproliferative natural product didemnin B is presented. In vitro protein biosynthesis inhibition potency and antitumor activity were evaluated. The results indicate that all four analogues are biologically active and could serve as photoaffinity reagents for the study of receptor-binding interactions of didemnins. These analogues could also be useful in studying antitumor effects of didemnins.

Stereoselective synthesis of a conformationally restricted β-hydroxy-λ-amino acid

Abstract β-Hydroxy-λ-amino acids are a class of non-proteinogenic amino acids present in many important biologically active natural products. In conjunction with our research on didemnins, we designed and synthesized a sterically constrained β-hydroxy-λ-amino acid in which the requisite carboxyl, hydroxyl and amino groups are positioned on a conformationally stable 6-membered ring.