Search for: All records

Abstract Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylatedCyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers. 

Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from Nocardiopsis, with a desymmetrized cyclo-D-Trp-D-Trp DKP core. Based on our deeper biosynthetic understanding, a biomimetic total synthesis of (+)-nocardioazine B is accomplished in merely seven steps and 23.2% overall yield. This pathway accesses regio- and stereoselectively C3-isoprenylated analogs of (+)-nocardioazine B, using the same number of steps and in similar efficiency. The successful strategy mandated that the biomimetic C3-prenylation step be executed early. The use of an unprotected carboxylic acid of Trp led to high diastereoselectivity toward formation of key intermediates exo-12a, exo-12b, and exo-12c (>19:1). Evidence shows that N1methylation causes the prenylation reaction to bifurcate away to result in a C2-normal-prenylated isomer. Nocardioazine A, possessing an isoprenoidal-epoxide bridge, inhibits P-glycoprotein (P-gp)-mediated membrane efflux, in multidrug-resistant mammalian colon cancer cells. As several P-gp inhibitors have failed due to their toxicity effects, endogenous amino-acid-derived noncytotoxic inhibitors (from the nocardioazine core) are worthy leads toward a rejuvenated strategy against resistant carcinomas. This total synthesis provides direct access to Trp-derived isoprenylated DKP natural products and their derivatives. 

Abstract The 2,5-diketopiperazines are a prominent class of bioactive molecules. The nocardioazines are actinomycete natural products that feature a pyrroloindoline diketopiperazine scaffold composed of two D-tryptophan residues functionalized byN- andC-methylation, prenylation, and diannulation. Here we identify and characterize the nocardioazine B biosynthetic pathway from marineNocardiopsissp. CMB-M0232 by using heterologous biotransformations, in vitro biochemical assays, and macromolecular modeling. Assembly of thecyclo-L-Trp-L-Trp diketopiperazine precursor is catalyzed by a cyclodipeptide synthase. A separate genomic locus encodes tailoring of this precursor and includes an aspartate/glutamate racemase homolog as an unusualD/Lisomerase acting upon diketopiperazine substrates, a phytoene synthase-like prenyltransferase as the catalyst of indole alkaloid diketopiperazine prenylation, and a rare dual function methyltransferase as the catalyst of bothN- andC-methylation as the final steps of nocardioazine B biosynthesis. The biosynthetic paradigms revealed herein showcase Nature’s molecular ingenuity and lay the foundation for diketopiperazine diversification via biocatalytic approaches.