Recent studies identified a short peptide motif that serves as a docking site for cyclin/cyclin-dependent kinase (cdk) 2 complexes. Peptides containing this motif block the phosphorylation of ...substrates by cyclin A/cdk2 or cyclin E/cdk2. Here we report that cell membrane-permeable forms of such peptides preferentially induced transformed cells to undergo apoptosis relative to nontransformed cells. Deregulation of E2F family transcription factors is a common event during transformation and was sufficient to sensitize cells to the cyclin/cdk2 inhibitory peptides. These results suggest that deregulation of E2F and inhibition of cdk2 are synthetically lethal and provide a rationale for the development of cdk2 antagonists as antineoplastic agents.
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC50s < 400 nM in a ...partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC50 < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD ≥ 100 mg/kg were selected for dose−response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.
Following earlier work on cystine-bridged peptides, cyclic phosphopeptides containing nonreducible mimics of cystine were synthesized that show high affinity and specificity toward the Src homology ...(SH2) domain of the growth factor receptor-binding protein (Grb2). Replacement of the cystine in the cyclic heptapeptide cyclo(CY*VNVPC) by d-α-acetylthialysine or d-α-lysine gave cyclo(Y*VNVP(d-α-acetyl-thiaK)) (22) and cyclo(Y*VNVP(d-α-acetyl-K)) (30), which showed improved binding 10-fold relative to that of the control peptide KPFY*VNVEF (1). NMR spectroscopy and molecular modeling experiments indicate that a β-turn conformation centered around Y*VNV is essential for high-affinity binding. X-ray structure analyses show that the linear peptide 1 and the cyclic compound 21 adopt a similar binding mode with a β-turn conformation. Our data confirm the unique structural requirements of the ligand binding site of the SH2 domain of Grb2. Moreover, the potency of our cyclic lactams can be explained by the stabilization of the β-turn conformation by three intramolecular hydrogen bonds (one mediated by an H2O molecule). These stable and easily accessible cyclic peptides can serve as templates for the evaluation of phosphotyrosine surrogates and further chemical elaboration.
Bengamide B, a novel sponge-derived marine natural product with broad spectrum antitumor activity, was not suitable for further preclinical development because of its difficult synthesis and very ...poor water solubility. Bengamide B produced a 31% T/C at its solubility-limited maximum intravenous dose of 33 μmol/kg in MDA-MB-435 breast carcinoma implanted subcutaneously as a xenograft in nude mice. Compound 8a, a bengamide B analogue with three structural changes (t-Bu alkene substituent, unsubstituted lactam nitrogen, and inverted lactam 5‘-myristoyloxy group), was as potent as bengamide B in vitro and more efficacious than bengamide B in vivo. A series of ester-modified analogues based on 8a were synthesized and tested in vitro and in vivo (MDA-MB-435). The cyclohexyl- and phenethyl-substituted esters, 8c and 8g, respectively, had in vitro and in vivo activities similar to that of 8a and enhanced water solubility (ca. 1 mg/mL). Consequently, 8c and 8g were tested in the MDA-MB-435 xenograft model at 100 μmol/kg and produced 29% and 57% tumor regression, respectively.
A series of α-substituted β-alanine (β*) linked polyamides (DbaPyPyPy-β*-PyPyPy) were prepared and examined. This resulted in the observation that while most substituents disrupt DNA binding, ...(R)-α-methoxy-β-alanine (β( R )-OMe) maintains strong binding affinity and preferentially adopts a hairpin versus extended binding mode, providing an alternative hairpin linker to γ-aminobutyric acid (γ). A generalized variant of a fluorescent intercalator displacement assay conducted on a series of hairpin deoxyoligonucleotides containing a systematically varied A/T-rich binding site size was developed to distinguish between the extended binding of the parent β-alanine 1 (DbaPyPyPy-β-PyPyPy) and the hairpin binding of 3 (DbaPyPyPy-β( R )-OMe-PyPyPy).
Total Syntheses of Bengamides B and E Kinder, Frederick R; Wattanasin, Sompong; Versace, Richard W ...
Journal of organic chemistry,
03/2001, Letnik:
66, Številka:
6
Journal Article
Recenzirano
Total syntheses of the cytotoxic marine natural products bengamides B and E are described. Both bengamides are prepared via amide coupling of a protected polyhydroxylated lactone intermediate 9 with ...a suitably substituted aminocaprolactam intermediate. Lactone 9 is prepared in five steps from commercially available α-d-glucoheptonic γ-lactone. The key reactions are a selective deprotection of a 1,2-acetonide in the presence of a 1,3-acetonide and an (E)-selective olefination of an unstable aldehyde using a gem-dichromium reagent. The bengamide B lactam intermediate 10 is prepared in seven steps from commercially available (5R)-5-hydroxy-l-lysine (12). The desired S-configuration at the γ-OH lactam position is established using the Mitsunobu reaction.
This paper outlines the results of a collaborative program begun in 1990 under the NIH National Cooperative Drug Discovery Group (NCDDG) program. It involves the unified research of a ...multi-institutional group from both academic and corporate laboratories. Our working hypothesis is that targets identified through basic molecular and cell biology studies are relevant for the treatment of human cancers. Thus, a broad range of primary biochemical assays have guided the examination of extracts obtained from marine organisms (both collected and cultured) and purified marine natural products. The goal is to discover small molecules effective against these biological targets. An ever-changing panel of assays focus on a number of cancer relevant targets associated with the cell cycle, signal transduction, angiogenesis or apoptosis. A massive library of materials has been assembled for evaluation in the screens and it consists of more than 900 compounds and 16,000 extracts. We believe that these samples have enormous potential for chemodiveristy and progress to date supports this contention. The first part of the paper focuses on highlights from the period 1995-1999. The two most important developments were that the bengamide and the psammaplin families provided important insights leading to the development of two compounds, LAF-389 and NVP-LAQ824. These were both advanced to Phase I anti-cancer clinical trials. A sampling of recent discoveries, including current leads in development is also discussed. Attention then turns to new technologies and strategies aimed at shortening the time interval from an initial lead candidate discovery to assessment of its future therapeutic potential.
A series of saturated heterocyclic analogues of distamycin were prepared and examined. A fluorescent intercalator displacement (FID) assay conducted on pdA–pdT DNA to obtain
C
50 values and a hairpin ...deoxyoligonucleotide containing an A/T-rich binding site was used to evaluate DNA binding affinity. It is observed that saturated heterocycles greatly reduce the DNA binding relative to distamycin.
A series of saturated heterocyclic analogues of distamycin was prepared and DNA binding affinity evaluated with a fluorescent intercalator displacement (FID) assay.
The structural chemistry and biological activity of the bengamide class of compounds have been further characterized. Extracts prepared from recollected Jaspis cf. coriacea from five sites in Fiji ...were pooled. Six new bengamides, M (7b), N (8a), O (8b), P (9a), Q (9b), and R (10), were identified, accompanied by the known bengamides A (1a), B (1b), E (3a), F (3b), Y (5), Z (6), L (7a), G (11a), H (11b), and I (12). The structures of the new compounds were determined from spectroscopic data, and some were additionally confirmed by semisynthesis. Cytotoxicity screening data were obtained from the NCI-DTP 60 cell screen for bengamides A, B, and P. Bengamides A and B were more potent than bengamide P, with average IC50 values of 0.046, 0.011, and 2.70 FM, respectively. The in vitro antitumor activity against MDA-MB-435 human mammary carcinoma was also determined for natural bengamides A, B, E, F, P, M, O, and Z and for synthetic samples of B and O. The best activity was observed for the natural bengamides A (IC50 = 1 nM) and O (IC50 = 0.3 nM).
Identification of E2F-1/Cyclin A antagonists Sharma, Sushil K.; Ramsey, Timothy M.; Chen, Ying-Nan P. ...
Bioorganic & medicinal chemistry letters,
09/2001, Letnik:
11, Številka:
18
Journal Article
Recenzirano
A simple method for the synthesis of a rationally designed (
S,S)-Pro-Leu-spirolactam scaffold is described. This was expanded to a small biased library of compounds mimicking the ‘ZRXL’ motif in ...order to identify E2F-1/Cyclin A antagonists. The synthesized compounds were evaluated in an E2F-1/Cyclin A binding assay and moderately active analogues were identified. In addition, the critical roles of Phe, Leu, Lys, and Arg residues of the identified motif were determined.
A small biased library of compounds was prepared in order to identify E2F-1/Cyclin A antagonists using a rationally designed (
S,S)-Pro-Leu-spirolactam scaffold.
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