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Biomedical subjects

M M Joullié

Publications and source records attributed to M M Joullié.

At least 19 recordsLinked to original sources
PubMed2006

Total synthesis and biological evaluation of ustiloxin natural products and two analogs.

Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.

Biological Products↗
PubMed2001

Investigations of the reaction mechanisms of 1,2-indanediones with amino acids.

The reaction mechanisms of amino acids with a new class of fluorogenic reagents were investigated. The structures of colored and fluorescent species formed in these reactions were partially confirmed by experimental evidence. Reaction intermediates, C-N-C 1,3-dipoles derived from imines, were trapped with dipolarophiles in 3 + 2 cycloadditions to form spiropyrrolidines.

Amino Acids↗
PubMed2001

Total syntheses of conformationally constrained didemnin B analogues. replacements of N,O-dimethyltyrosine with L-1,2,3,4-tetrahydroisoquinoline and L-1,2,3,4-tetrahydro-7-methoxyisoquinoline.

The design and synthesis of two conformationally constrained analogues of didemnin B are described. The [N,O-Me(2)Tyr(5)]residue of didemnin B was replaced with L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) and L-1,2,3,4-tetrahydro-7-methoxyisoquinoline-3-carboxylic acid (MeO-Tic), which mimic the N,O-dimethylated tyrosine while constraining the conformation of the molecule. Preliminary results indicate that the conformation of the [N,O-Me(2)Tyr(5)]residue closely matches the conformation imposed by the Tic replacement.

Depsipeptides↗
PubMed2001

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.

Antineoplastic Agents↗
PubMed2001

Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs.

Tamandarins A (1) and B (2), two natural products similar in structure to didemnin B (3), were recently isolated from a Brazilian marine ascidian of the family Didemnidae. The cytotoxicity of 1 was reported to be somewhat more potent in vitro than that of 3 against various human cancer cell lines. The present account describes the first total syntheses of 1 and 2, and the syntheses of tamandarin A side chain analogues. The cytotoxicity data for these compounds show that the side chain modifications exhibit a parallel effect for both didemnins and tamandarins. This observation supports tamandarins' role as didemnins' mimic.

Animals↗
PubMed2001

Total synthesis of a conformationally constrained didemnin B analog.

The total synthesis of a didemnin B analogue containing a conformationally constrained replacement for the isostatine moiety is reported. Synthetic highlights include an improved preparation of 2-hydroxy-3-cyclohexenecarboxylic acid and a new strategy for accessing the macrocycle.

Animals↗
PubMed2001

Structure--activity relationships of side-chain modified didemnins.

The synthesis and antitumor activity of a novel didemnin B analogue containing a psi[CH2NH] amide bond surrogate between N-Me-D-Leu7 and Pro8 are reported. The analogue shows activity (GI50 = 4 nM) comparable to that of didemnin B (GI50 = 13 nM) in the NCI-60 tumor cell screen. This result, along with new data from previously reported synthetic didemnin analogues, is discussed within the context of the side-chain SAR for didemnins.

Antineoplastic Agents↗
PubMed2001

[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.

Affinity Labels↗
PubMed2000

Progress toward the total synthesis of callipeltin A (I): asymmetric synthesis of (3S,4R)-3,4-dimethylglutamine.

[reaction:see text] During the total synthesis of the novel cyclic depsipeptide callipeltin A (1), the unit (3S,4R)-3,4-dimethylglutamine, was successfully synthesized by asymmetric Michael addition and subsequent electrophilic azidation. The key feature of this approach is the generation of three adjacent stereogenic centers using the same camphorsultam chiral auxiliary.

Depsipeptides↗
PubMed2000

Inhibition of protein synthesis by didemnins: cell potency and SAR.

Synthetic and naturally occurring didemnins are potent and specific inhibitors of protein synthesis in vitro. Structure-activity analysis indicates a requirement for the intact macrocycle; however, the smaller ring size represented by the didemnin analogue, tamandarin A, is equipotent to didemnin B. Replacement of the N,O-dimethyltyrosine by a N-methylphenylalanine or N-methylleucine residue is also well-tolerated. The rank order for inhibition of protein synthesis in vitro appears to be retained in MCF-7 cells, albeit at much higher potency. This increase in potency is explained for the first time by data indicating that MCF-7 cells can accumulate didemnin B up to 2-3 orders of magnitude compared to the growth medium.

Animals↗
PubMed2000

Inhibition of protein synthesis by didemnin B: how EF-1alpha mediates inhibition of translocation.

The antineoplastic cyclic depsipeptide didemnin B (DB) inhibits protein synthesis in cells and in vitro. The stage at which DB inhibits protein synthesis in cells is not known, although dehydrodidemnin B arrests translation at the stage of polypeptide elongation. Inhibition of protein synthesis by DB in vitro also occurs at the elongation stage, and it was shown previously that DB prevents EF-2-dependent translocation in partial reaction models of protein synthesis. This inhibition of translocation displays an absolute requirement for EF-1alpha; however, the dependence upon EF-1alpha was previously unexplained. It is shown here that DB binds only weakly to EF-1alpha/GTP in solution, but binds to ribosome. EF-1alpha complexes with a dissociation constant K(d) = 4 microM. Thus, the inhibition of protein synthesis by DB appears to involve an interaction with both EF-1alpha and ribosomes in which all three components are required. Using diphtheria toxin-mediated ADP-ribosylation to assay for EF-2, it is demonstrated that DB blocks EF-2 binding to pre-translocative ribosome.EF-1alpha complexes, thus preventing ribosomal translocation. Based on this model for protein synthesis inhibition by DB, and the proposed mechanism of action of fusidic acid, evidence is presented in support of the Grasmuk model for EF-1alpha function in which this elongation factor does not fully depart the ribosome during polypeptide elongation.

Animals↗
PubMed1999

The first total synthesis of (-)-tamandarin A.

[formula: see text] Tamandarin A (1), a newly isolated natural product similar in structure to didemnin B (2), was shown to be somewhat more active in vitro than 2 against pancreatic carcinoma with an ED50 value 1.5 to 2 ng/mL. We report here the first total synthesis of 1. The key steps include a practical stereoselective synthesis of the Hiv-isostatine unit, high-yielding linear precursor formation, a successful macrocyclization, and coupling of the macrocycle with the side chain to afford tamandarin A (1).

Antineoplastic Agents↗
PubMed1998

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.

Animals↗
PubMed1997

A basic compositional requirement of agents having heparin-like cell-modulating activities.

Heparin has been recognized as possessing a large variety of cell-modulating activities. Using compositionally simple, structurally rigid, and low molecular weight saccharide molecules (cyclodextrins), we demonstrated that these activities depend primarily on a single, gross compositional parameter: a minimum intramolecular density of neighboring anionic (sulfate) groups. This same critical parameter is shown to be involved in achieving cell-modulating behavior as diverse as angiogenesis, endothelial proliferation, inhibition of smooth muscle cell growth, and cell protection against virus invasion. Physical chemical evidence is presented that associates this property with multi-ionic complex formation between the clusters of anionic and cationic sites on the complexing partners. These observations revive early suggestions of the decisive role of electrostatic complexation capabilities of glycosaminoglycans like heparin; taken together with numerous observations on heparinoids and other agents reported in diverse specialized fields of cell biology and medicine, they provide evidence that molecular agents of critical anionic (sulfate) density (MACADs) represent a broad class of molecules that, in contrast to proteins, do not rely on structural detail for their cell biological activities, but function by ionic complexation with proteinic agents (e.g. growth factors), thereby modifying their structure-specific activities.

Alcian Blue↗
PubMed1995

The cyclic depsipeptide backbone of the didemnins.

An X-ray crystal analysis of phi-lactone N-¿1-¿N-¿4-¿[3- hydroxy-5-methyl-1-oxo-4-(N-L-threonylamino)heptyl]- oxy¿-2,5-dimethyl-1,3-dioxohexyl¿-L-leucyl¿-L-prolyl¿- N,O-dimethyl-L-tyrosine hydrobromide hydrate (1a), C42H66N5O11+.Br-.H2O, was obtained in order to determine the backbone folding of the macrocycle and to compare the results obtained with those reported previously for the natural product didemnin B (1b). Some differences were noted in the torsion angles of the two conformers of the hydrobromide salt, denoted (1a) and (1a'). The conformation of (1a') resembled the conformation of (1b) more closely than did that of (1a). Certain regions of both crystal backbones were more flexible than those in didemnin B; however, the transannular hydrogen bonds in both (1a) and (1a') were somewhat stronger than in (1b).

Amino Acid Sequence↗