Design and Synthesis of Heterocycle‐Fused Enediyne Prodrugs Activable at Will

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Synthesis of N-Fused \u201cLactendiynes\u201d

New \u201clactendiynes\u201d, characterized by the fusion at C-4 and N-1 of a \u3b2-lactam with a hydroxylated 10-membered cyclic enediyne, were synthesized. Studies on their reactivity have shown that this type of fusion with the azetidinone represents a sufficient \u201csafety-catch\u201d against cycloaromatization. These compounds are relatively reactive toward basic hydrolysis, affording monocyclic enediynes which undergo fast cycloaromatization at room temperature

Intramolecular transamidation of \u3b2-lactams as a means for the enzymatic control of ring opening: Effect of substituents on the rate of reaction

A series of simple monocyclic \u3b2-lactams bearing side-chains, containing amino groups, have been synthesized, and the rate of their intramolecular transamidation studied. Protection of the amino group with an enzymatically cleavable group, allows us to selectively control the ring enlargement process

The proliferative response of HT-29 human colon adenocarcinoma cells to bombesin-like peptides

Bombesin-like peptides (BLP) and their receptors are widely distributed throughout the intestine and are potential mitogens for gastrointestinal cancers. In this study we characterized the proliferation induced by BLP in the human adenocarcinoma cell line HT-29. The number of HT-29 cells, partially serum deprived (1% fetal bovine serum) for 48 h, was increased after 24 h of stimulation with bombesin, GRP, neuromedin B (NMB) and neuromedin C (NMC) ranging from 0.1 nM up to 1 muM. Reverse transcription polymerase chain reaction studies, revealed the presence of mRNA for NMB and for the GRP preferring receptor (GRP-R). mRNA for GRP, NMB preferring receptor (NMB-R) and bombesin receptor subtype 3 (BRS-3) were not detected. [D-Phe(6)]bombesin-(6-13)methyl ester (Al) and BIM-23127 (A2), are considered as inhibitors of binding to GRP-R and NMB-R, respectively. Surprisingly, A I and A2 stimulated the proliferation of HT-29 cells. Moreover, in the simultaneous presence of 1 muM Al and 0.1 muM GRP or 0.1 nM or 0.1 muM bombesin, inhibition of the proliferation was observed. Our data demonstrate that the proliferation induced by BLP in HT-29 cells is due to interaction with the GR-P-R. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved

Synthesis of a key intermediate for Thienamycin and Imipenem through stereoselective two-direction elongation of asymmetrized bis(hydroxymethyl)acetaldehyde (BHYMA 17)

The enantioselective formal synthesis of Thienamycin and Imipenem has been realised through two-direction elongation of the chiral building block bis(hydroxymethyl)acetaldehyde 5. The generation of the two additional stereocentres has been carried out with excellent diastereoselectivity thanks to two sequential \u201cprotecting group controlled\u201d nucleophilic additions. Another key step was represented by the regioselective oxidation of a primary-secondary 1,3-diol to the corresponding \u3b2-hydroxyacid

Highly Versatile Stereoselective Synthesis of All Eight Stereoisomers of Branched-Chain Triols Starting from Asymmetrized Bis(hydroxymethyl)acetaldehydes (BHYMA)

All possible stereoisomers of triols of general formula 6 (R1 = allyl, R2 = Me or allyl) have been synthesized stereoselectively starting from asymmetrized bis(hydroxymethy1)acetaldehyde (BHYMA*), a novel chiral building block prepared through a chemoenzymatic methodology. This goal was realized through a sequence of protecting group-controlled nucleophilic additions and/or reductions performed on two side arms of this versatile building block