Design and concise synthesis of novel vitamin D analogues bearing a functionalized aromatic ring on the side chain

Five novel vitamin D analogues (2a, 2b, 3a, 3b and 4) bearing an aromatic side chain have been designed and synthesized in a convergent manner. The requisite CD-ring synthons (10a–c) were prepared from C22 aldehyde (5) using four- or five-step procedures. Using turbo-Grignard reagents allowed aromatic side chains with a polar functional moiety to be installed in a single step with excellent yields. A preliminary biological evaluation using bovine thymus vitamin D receptor (VDR) suggested that incorporating a carboxylic acid instead of the C25-hydroxy group had a positive effect on the VDR affinity compared with the corresponding esters.     

Design,synthesis and biological evaluation of new rhodacyanine analogues as potential antitumor agents

In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring（5a-5h）,the isoquinolinium ring（6a-6c） and the quinolinium ring（7a-7e） linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line（H460） by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC₅₀ values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC₅₀ = 0.006μmol/L) was 216.7 times more active than MKT-077(IC₅₀ = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.     

Vitamin D and click chemistry. Part 1: A stereoselective route to vitamin D analogues with triazole rings in their side chains

Efficient preparation of vitamin D CD ring system synthons with triazole rings in their side chains is based on the formation of the triazole ring from a [3+2]-cycloaddition of a vitamin D side chain terminal azide with a terminal acetylene.     

Design, synthesis, and biological properties of highly potent tubulysin D analogues

Ten analogues of tubulysin D were synthesized and assayed against established mammalian cell lines, including cancer cells measuring inhibition of cell growth by an MTT assay. These experiments establish for the first time the essential features for the potent cytotoxicity of tubulysin D. The activities of analogues 2 to 5 demonstrate that numerous modifications may be introduced at the C-terminus of the natural product with only modest loss in activity, while the activities of analogues 6 to 8 suggest that a basic amine must be present at the N-terminus to maintain activity. Most surprisingly, analogue 10 establishes that replacement of the chemically labile O-acyl N,O-acetal with the stable N-methyl group results in almost no loss in activity. In aggregate, these structure-activity relationships enable the design of analogues such as 11 that are smaller and considerably more stable than tubulysin D but that maintain most of its potent cell-growth inhibitory activity.     

The thioacetate approach to the synthesis of the side chain of vitamin D metabolites and analogues

We describe an efficient synthesis of thia analogues of the vitamin D side chain that is based on the in situ generation of a thiolate anion and its alkylation with electrophiles.     

Design,synthesis, and in vitro antifungal evaluation of novel triazole derivatives bearing alkynyl side chains

In order to explore novel antifungal agents, twenty-seven triazole derivatives featuring an alkyne linker in the side chain were designed and synthesized by the Sonogashira reaction. Most of the target compounds exhibited good antifungal activity against eight human pathogenic fungi, especially excellent activity against Candida and Cryptococcus species, comparing with the reference drugs fluconazole, voriconazole and ravuconazole. Compounds A2 and A3 exhibited in vitro activity against all the tested fungi with MIC₈₀ values ranging from 0.0156 μg/mL to 0.5 μg/mL, which are superior to ravuconazole and fluconazole. SAR and molecular docking study give a clear conclusion that para-fluoro, para-chloro, and para-cyano substituted phenylalkynyl or pyridinylalkynyl side chains may promote triazole antifungal activity.     

Systematic solution-phase parallel synthesis of active vitamin D3 analogs with elongated side chains and their cell differentiation activities

Side-chain elongation of active vitamin D3 is acknowledged as a structural modification to enhance its cell differentiation activity; however, the comprehensive structure-activity relationship (SAR) as a result of this modification has not been reported. To clarify the SAR, we synthesized six analogs systematically elongated at the 24-position, 26,27-position, or both by methylene (normal A-ring series 1a-f) in a facile parallel solution-phase synthesis. Using parallel synthesis, we expanded the side chain-elongation study into two 19-exomethylene analog series: 19-nor-A-ring (4a-f) and 2-methylene-19-nor-A-ring (5a-f). In the 19-nor-A-ring analog series, the SAR induced by side-chain elongation was similar to the normal A-ring analog series, but in the 2-methylene-19-nor-A-ring series, the SAR was unique.     

Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications

We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-l-prolinal as a key step. Barbier-type allylation of N-Boc-l-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in vitro.     

Star-shaped ethynylpyrimidine with long alkoxyl side chains: synthesis, fluorescence and 2D self-assembling

In this contribution, we describe the synthesis of a star shaped ethynylpyrimidine having long alkoxyl side chains using Suzuki cross-coupling reactions. This compound presents interesting blue light emission fluorescence as well as self-assembling properties on graphite: a chiral system is obtained starting from a nonchiral molecule. This preliminary work indicates that pyrimidine derivatives could be good candidates for the development of novel functional organic materials.     

Synthesis,characterization, and polymerization of propenyl ether analogues

A series of aromatic monomers bearing cationically polymerizable propenyl groups were prepared and characterized using the readily available starting materials: isoeugenol and o-allyl phenol. Monomers with both propenyl and vinyl ether functional groups were also synthesized by the reaction of these starting materials with chloroethyl vinyl ether. The reactivity of the resulting monomers in photoinitiated cationic polymerization was studied using differential scanning photocalorimetry and photogel point measurements. Their thermal properties were determined using thermogravimetric analysis. © 1994 John Wiley & Sons, Inc.     

Synthesis and luminescence of polyphosphazenes with carbazolyl side chains

Two new blue‐light‐emitting polyphosphazenes ( 1 and 2 ) containing carbazolyl groups as side chains were synthesized from a highly reactive macromolecular intermediate by a nucleophilic substitution reaction. Molecular structural characterization for the polymers was presented by ¹H NMR, IR, and ultraviolet–visible spectra, gel permeation chromatography, and differential scanning calorimetry. The polymers exhibited excellent solubility in common organic solvents and were thermally stable. A fluorescence analysis of the two materials in tetrahydrofuran showed a strong blue light emitting. The quantum yields of the polyphosphazenes were 0.55 for 1 and 0.64 for 2 , relative to quinoline (in 0.1 N H₂SO₄). An electroluminescent diode was fabricated, and a bright blue light was observed; the maximum external quantum efficiency was about 0.026% at an applied forward voltage of 23 V. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3428–3433, 2001     

Molecular mechanics-based conformational analysis of previtamin D and its A-ring analogues

Summary The ground-state conformational analysis of previtamin D and analogues with different substituents at C-3, C-1, and C-10 have been performed by force-field calculations. Differences in the photochemistry of these analogues are discussed in view of the concept of ground-state conformational control in photochemical reactions. The effect of complexes of previtamin D with silanol derivatives, formedvia hydrogen bonds, on their conformational equilibrium has been calculated. An increase in the population ofcZc conformers with increasing size of the silanol molecules (as a model for a heterogeneous silica surface) was observed.

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Konformationsanalyse von Previtamin D und seiner A-Ring-Analogen mit Hilfe von Kraftfeldrechnungen

Zusammenfassung Eine Konformationsanalyse des Grundzustandes von Previtamin D and von an C-1, C-3 und C-10 substituierten Analogen wurde mit Hilfe von Kraftfeldrechnungen durchgeführt. Unterschiedliches Reaktionsverhalten bei den photochemischen Umsetzungen dieser Verbindungen werden unter dem Gesichtspunkt der Grundzustandskontrolle von photochemischen Reaktionen diskutiert. Der Einfluß von Komplexbildung über Wasserstoffbrücken von Previtamin D mit Silanolen wurde berechnet. Eine Zunahme der Population dercZc-Konformeren mit zunehmender Größe des Silanols (ein Modell für eine heterogene Kieselgeloberfläche) wurde dabei beobachtet.

     

A simple and rapid synthesis of nucleotide analogues containing a phosphorothioate moiety at the terminal position of the phosphate chain

A straightforward method for the synthesis of nucleotide analogues bearing a phosphorothioate moiety at the terminal position of the polyphosphate chain is described. Several nucleoside 5′-(2-thiodiphosphates) and 5′-(3-thiotriphosphates) were synthesized by treatment of the appropriate nucleotide imidazolide derivative with a ca. 4-fold excess of thiophosphate triethylammonium salt in DMF in the presence of zinc chloride. The HPLC reaction yields varied from 80% to 100%, in the majority of cases exceeding 90%. Separation was accomplished by Sephadex ion-exchange chromatography or reverse-phase HPLC with preparative yields of about 70%.     

Design, synthesis, and evaluation of carbamate-substituted analogues of (+)-discodermolide

[Structure: see text] The design, syntheses, and biological evaluation of 22 totally synthetic analogues of the potent microtubule-stabilizing agent (+)-discodermolide (1) have been achieved. Structure-activity relationships of the C(19) carbamate were defined, exploiting two synthetically simplified scaffolds, as well as the parent (+)-discodermolide framework.     

Design, total synthesis, and evaluation of novel open-chain epothilone analogues

[structure: see text] The design, total synthesis, and biological evaluation of two open-chain analogues of epothilone incorporating the critical C1-C8 fragment and the aromatic side chain held together by a small molecular scaffold have been achieved. Biological evaluation revealed that further restraint between the flexible C1-C8 region and the molecular scaffold may be necessary for potent inhibition of cell proliferation.     

Total synthesis and biological evaluation of marinopyrrole A and analogues

A five-step total synthesis of the antibiotic marinopyrrole A (1) is described. The developed synthetic technology enabled the synthesis of several marinopyrrole A analogs whose antibacterial properties against methicillin-resistant Staphylococcus aureus TCH1516 were evaluated.     

Synthesis of novel analogues of 1alpha,25-dihydroxyvitamin D(3) with side chains at C-18

Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).     

Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity

A series of melodorinol analogues were synthesized via a diverted total synthesis approach, leading to structural modifications on several regions of the molecule. Their cytotoxicity was evaluated against five human cancer cell lines (KB, HeLa-S3, MCF-7, HT-29 and A549). Structure-activity relationship studies revealed key parameters that affect the cytotoxicity. In particular, the novel 4-bromo-furanone analogues exhibited greater cytotoxicity compared to the corresponding non-brominated analogues. The stereochemistry at C-6 and the nature of acyl substituents on the C-6 and C-7 hydroxyl groups also play an important role. The most potent analogues exhibit approximately 15-fold higher cytotoxicity towards KB and HeLa-S3 than melodorinol and also show exceptionally high potency against MCF-7, HT-29 and A549 cell lines.