Novel A-ring homodimeric C-3-carbamate analogues of 1alpha,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation

The synthesis of a new class of vitamin D3 analogues in which two units of 1alpha,25-dihydroxyvitamin D3 are linked at the C-3 position by a dicarbamate functionality of variable length is described. The analogues demonstrated no affinity for the vitamin D receptor and possessed no antiproliferative or transactivating properties.     

Synthesis and biological evaluation of C-3'NH/C-10 and C-2/C-10 modified paclitaxel analogues

Concurrent modifications on the C-3'NH/C-10, and C-2/C-10 positions on paclitaxel were carried out as a way of investigating possible synergistic effects. The biological activities of these analogues were evaluated in both a microtubule assembly assay and human ovarian cancer (A2780) and prostate cancer (PC3) cytotoxicity assay. In some cases the doubly modified analogues were more active than would have been predicted based on the activity of the singly modified analogues, indicating probable synergistic effects.     

The synthesis and antibacterial activity of totarol derivatives. Part 2: Modifications at C-12 and O-13

Alterations of the C-12 and C-13 aromatic ring substituents of totarol (1) afforded the series of derivatives 2-14, and introduction of substituents at C-12 gave exclusively 2a-14a. The majority of these analogues were tested in vitro against the following organisms: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multiresistant Klebsiella pneumoniae. The results were evaluated in terms of structure-activity relationship which reveals that: (a) the phenolic moiety at C-13, in general, is essential for antibacterial activity at < 32 microg/mL against gram-positive species, and (b) derivatization at C-12 has an undesirable effect on the antibacterial activity of this class of compounds, while (c) all compounds tested are ineffective against the gram-negative Klebsiella pneumoniae.     

Synthesis of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues modified at the C-4 and C-9 positions and their behaviour towards sialidase from influenza virus and pig liver membrane

The synthesis of novel 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues structurally varied at C-4 and C-9 by transformation from versatile key intermediates and their inhibitory activity against sialidase from influenza virus A and pig liver membrane are described.     

Synthesis and biological evaluation of rebeccamycin analogues modified at the imide moiety

Glycosylated indolocarbazoles related to the antibiotic rebeccamycin represent an important class of antitumour drugs. In the course of our structure-activity relationship studies, new rebeccamycin analogues modified at the imide moiety were synthesised. The antiproliferative activity of the compounds was evaluated on three human cancer cell lines, A2780 (ovarian cancer), H460 (lung cancer), and GLC4 (small-cell lung cancer). The in vitro cytotoxicity of compounds 2 and 4, characterised respectively by a 1,3-dioxolan and (1,3-dioxolan-4-yl)methylene groups linked to the imide moiety, was higher than the reference compound, edotecarin. The effect of compound 2 in inducing tumour regression in the A2780 xenograft model was also investigated.     

Novel azalides derived from 16-membered macrolides. Part II: Isolation of the linear 9-formylcarboxylic acid and its sequential macrocyclization with an amino alcohol or an azidoamine

The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macrolides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously reported. Sequential macrocyclization of the formylcarboxylic acid with amino alcohol followed by deprotection afforded corresponding 14- to 16-membered azalides. On the other hand, reductive amination of the formylcarboxylic acid with an azidoamine followed by macrolactam formation with an amine generated from the azide gave 14- to 16-membered azalactams. Among these derivatives, 15-membered azalactams and 16-membered azalides exhibited characteristic in vitro antibacterial activities. Although optimization of 15-membered azalactams including demycarosyl analogues did not provide remarkably promising molecules, SAR studies of 16-membered azalides disclosed that substitution at the 15 position was very important for identification of a clinical candidate.     

Design and synthesis of novel leucomycin analogues modified at the C-3 position. Part II: 3-O-(3-Aryl-2-propenyl)leucomycin analogues

The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully protected intermediate (5), appropriate modifications including Heck reaction were performed to furnish 3-O-(3-aryl-2-propenyl)leucomycin A(7) analogues (9a-9m). These leucomycin A(7) derivatives showed improved in vitro antibacterial activities against clinically important pathogens including erythromycin-resistant Streptococcus pneumoniae (ERSP). SAR analysis of derivatives modified at the C-3 and C-3' positions suggested that single modification at C-3 or C-3' was effective for in vitro antibacterial activity.     

Synthesis and evaluation of novel pseudomycin side-chain analogues. Part 3.

To increase the therapeutic utility of C-18 side-chain bearing pseudomycin analogue 2, we prepared additional analogues and prodrugs of 2 containing further modifications at various positions within its core structure. Each of the newly synthesized derivatives (10-15) exhibited reduced tail vein toxicity relative to the parent compound. Some of the new pseudomycin derivatives (e.g., 14) also showed improved in vivo antifungal activity relative to its corresponding parent compound.     

Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-dehydro-(S)-proline (Δ³Pro), azetidine-3-carboxylic acid (3Aze) and dehydro-alanine (ΔAla) have been used to prepare [Δ³Pro²]EM-2 (1), [Aze²]EM-1 (2), [Aze²]EM-2 (3), [3Aze²]EM-1 (4), [3Aze²]EM-2 (5) and [ΔAla²]EM-2 (6). Binding assays and functional bioactivities for μ- and δ-receptors are reported. The highest affinity, bioactivity and selectivity are shown by peptides 2 and 3 containing the Aze residue.     

Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2)

Salvinorin A is the only known non-nitrogenous and specific kappa-opioid agonist. A series of salvinorin A derivatives were prepared and tested for in vitro activity at the kappa-opioid receptor. Unsubstituted carbamate 9 was a potent kappa-agonist (EC(50) = 6.2 nM) and should be more stable than salvinorin A toward metabolic transformations. Compound 10, containing an N-methyl carbamate at C(2), showed partial agonist activity with 81% efficacy when compared with the full agonist U50,488H. No antagonist ligands were observed.     

Novel analogs of D-e-MAPP and B13. Part 1: synthesis and evaluation as potential anticancer agents

A series of novel isosteric analogs of the ceramidase inhibitors, (1S,2R)-N-myristoylamino-phenylpropanol-1 (d-e-MAPP) and (1R,2R)-N-myristoylamino-4'-nitro-phenylpropandiol-1,3 (B13), with modified targeting and physicochemical properties were designed, synthesized, and evaluated as potential anticancer agents. When MCF7 cells were treated with the analogs, results indicated that the new analogs were of equal or greater potency compared to the parent compounds. Their activity was predominantly defined by the nature of the modification of the N-acyl hydrophobic interfaces: N-acyl analogs (class A), urea analogs (class B), N-alkyl analogs (class C, lysosomotropic agents), and omega-cationic-N-acyl analogs (class D, mitochondriotropic agents). The most potent compounds belonged to either class D, the aromatic ceramidoids, or to class C, the aromatic N-alkylaminoalcohols. Representative analogs selected from this study were also evaluated by the National Cancer Institute In Vitro Anticancer Drug Discovery Screen. Again, results showed a similar class-dependent activity. In general, the active analogs were non-selectively broad spectrum and had promising activity against all cancer cell lines. However, some active analogs of the d-e-MAPP family were selective against different types of cancer. Compounds LCL85, LCL120, LCL385, LCL284, and LCL204 were identified to be promising lead compounds for therapeutic development.     

Novel 3-amino-2-hydroxy acids containing protease inhibitors. Part 1: Synthesis and kinetic characterization as aminopeptidase P inhibitors

Novel, potent inhibitors of aminopeptidase P, containing a 3-amino-2-hydroxy acid and a proline or a proline analogues, have been prepared. One part of the bestatin-derived inhibitors was found to inhibit APP from Escherichia coli and from rat intestine according to a mixed-type mechanism, with Ki values up to 1.26 microM. The other compounds, 3-amino-2-hydroxy acyl prolines of a different configuration, inhibit APP competitively, according to a slow-binding mechanism, with Ki values in the nanomolar up to the micromolar range.     

Synthesis and biological evaluation of C-12 triazole and oxadiazole analogs of salvinorin A

Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ-opioid receptor (KOPR) agonist. A series of C-12 triazole analogs and the oxadiazole (4) analog of 1 are synthesized and screened for binding affinity at κ, μ (MOPR), or δ (DOPR). Surprisingly, all triazole analogs have shown negligible binding affinity at opioid receptors and the oxadiazole 4, a reported MOPR and KOPR antagonist, exhibits very low affinities to opioid receptors and no antagonism in our binding assays. These results suggest that electronic factors that may affect either the electron density of hydrogen bond acceptor at C-12 or hydrophobic interactions between C-12 moiety and KOPR are critical to C-12 analog’s affinity for KOPR.     

Synthesis of methyl 4'-O-methyl-13C12-beta-D-cellobioside from 13C6-D-glucose. Part 1: reaction optimization and synthesis

A high yielding synthetic route for methyl 4'-O-methyl-beta-D-cellobioside starting from d-glucose was established. The reaction conditions optimized with nonlabeled materials were used for the synthesis of methyl 4'-O-methyl-13C12-beta-D-cellobioside, a compound having more than 99% 13C enrichment at each of the twelve pyranose carbon atoms. The labeled compound is required to study the hydrogen bond network of cellodextrins and cellulose by CPMAS NMR experiments.     

Synthesis and biological evaluation of novel 1beta-methylcarbapenems having a new moiety at C-2.

The synthesis and biological activity of the novel series of 1 beta-methylcarbapenems 1a-f, bearing a variety of 3",4"-disubstituted pyrrolidinamides as substituents at C-2, are described. Of these carbapenems, diol 1a showed the most potent and well balanced antibacterial activity against Gram-positive and Gram-negative. 1a was also evaluated for pharmacokinetics and in vivo therapeutic efficacy in systemic infections.     

2-Deoxy-2,3-didehydro-N-acetylneuraminic acid analogues structurally modified at the C-4 position: synthesis and biological evaluation as inhibitors of human parainfluenza virus type 1

To explore the influence of binding to human parainfluenza virus type 1 (hPIV-1), a series of 4-O-substituted Neu5Ac2en derivatives 6a-e was synthesized and tested for their ability to inhibit hPIV-1 sialidase. Among compounds 6a-e, the 4-O-ethyl-Neu5Ac2en derivative 6b showed the most potent inhibitory activity (IC50 6.3 microM) against hPIV-1 sialidase.     

Synthesis of encoded modified oligonucleotide libraries. Part 1: orthogonal chemistry

The basis for further development of combinatorial libraries of modified oligonucleotides tagged by a codifying sequence is discussed. The chemistry involved in the orthogonal synthesis of both strands and some representative examples of building blocks are presented.     

Novel TSAO derivatives modified at positions 3" and 4" of the spiro moiety.

We have explored the introduction of different functional groups at positions 3" and 4" of the spiro moiety of TSAO-T. Alkylation of this spiro moiety afforded mixtures of N and/or C-alkylated derivatives, while acylation occurs, exclusively, on the amino group. Position 3" has been selectively functionalized by halogenation followed by Stille-cross coupling reaction with organostannanes under a variety of experimental conditions.     

Synthesis and bioactivity of chemotactic tetrapeptides: fMLF-OMe analogues incorporating spacer aminoacids at the lateral positions

A small library of N-For and N-Boc tetrapeptidic analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMe (fMLF-OMe), obtained by incorporating three different spacer aminoacids (Gly, βAla and Pro) between the native residues of Met and Leu (N-For- and N-Boc-Met-Xaa-Leu-Phe-OMe; Xaa² series) and Leu and Phe (N-For- and N-Boc-Met-Leu-Xaa-Phe-OMe; Xaa³ series), have been synthesized and examined for their biological activity as agonists and antagonists. Chemotaxis, lysozyme release and superoxide anion production have been measured. All the N-For analogues maintain good to moderate chemotactic activity with the βAla³ 15 model reaching the maximum value. All the N-Boc tetrapeptides are efficient chemotactic antagonists. Conversely, with the exception of the moderate antagonistic activity exhibited by the N-Boc Xaa² models against lysozyme release, all the other N-Boc analogues do not show significant activity against both superoxide anion and lysozyme release.     

Synthesis and Cytotoxic Evaluation of Novel Thiazolocarbazoles. Part II1

Novel thiazolocarbazole derivatives have been synthesized via the corresponding imino-1,2,3-dithiazoles. In vitro antitumor activity of these polyheterocyclic compounds was studied.