A-ring Analogues Research Articles

Solid-phase peptide synthesis of analogues of the N-terminus A-ring fragment of the lantibiotic nisin: Replacements for the dehydroalanine (Dha) residue at position 5 and the first incorporation of a thioamide residue

A number of A-ring analogues of the lantibiotic nisin, containing replacements for the Dha residue at position 5, have been successfully prepared by solid-phase peptide synthesis. The Dha replacements include glycine, alanine, phenylalanine, serine and 1-aminocyclopropyl carboxylic acid (ACCa). The incorporation of a thioamide-isoleucine residue at position 4 is also described and represents the first reported preparation of a lantibiotic ring fragment containing a thioamide link.

Overcoming naphthoquinone deactivation: rhodium-catalyzed C-5 selective C–H iodination as a gateway to functionalized derivatives

We report a Rh-catalyzed method for the C-5 selective C-H iodination of naphthoquinones and show that complementary C-2 selective processes can be achieved under related conditions. C-C bond forming derivatizations of the C-5 iodinated products provide a gateway to previously inaccessible A-ring analogues. The present study encompasses the first catalytic directed ortho-functionalizations of simple (non-bias) naphthoquinones. The strategic considerations outlined here are likely to be applicable to C-H functionalizations of other weakly coordinating and/or redox sensitive substrates.

ChemInform Abstract: Synthesis of 6‐s‐Cis and 6‐s‐Trans A‐Ring Modified Vitamin D Analogues

AbstractReview: 143 refs.

Synthesis of 6-s-cis and 6-s-trans A-ring modified vitamin D analogues.

Vitamin D, through its hormonally active form 1α,25-dihydroxyvitamin D3 [1α,25- (OH)2-D3], exhibits a much broader spectrum of bio logical activities than expected in the endocrine system. However, 1α,25-(OH)2-D3 causes hypercalcemia a t pharmacologically r elevant doses wh ich forms a major obstacle in the clinical development of this compound. As a result, considerable effort has been made toward the synthesis of potential chemotherapeutic structurally related congeners with dissociation of beneficial effects from their toxic effects. Most of the analogues prepared have modifications on the upper side chain, more accessible from a synthetic point of view. Modifications of the A-ring are less extensive, although A-ring analogues exhibit a unique biological profile. This seco steroid can undergo a rotation around the 6,7 carbon-carbon single bond generating a wide array of molecular shapes, extending from the 6-s-cis to the more stable extended 6-s-trans conformation, which plays an important role in modulating the different biological activities of vitamin D. We review here, the synthetic strategies for the preparation of Vitamin D analogues with modific ations on the A-ring, including 6-s-cis locked derivatives that became of interest to further probe the less well investigate membrane actions of 1α,25-(OH)2-D3 for structure-activity relationship studies.

Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.

A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.

The Synthesis and Antimicrobial Activity of Heterocyclic Derivatives of Totarol.

The synthesis and antimicrobial activity heterocyclic analogs of the diterpenoid totarol are described. An advanced synthetic intermediate with a ketone on the A-ring is used to attach fused heterocycles and a carbon-to-nitrogen atom replacement is made on the B-ring by de novo synthesis. A-ring analogs with an indole attached exhibit, for the first time, enhanced antimicrobial activity relative to the parent natural product. Preliminary experiments demonstrate that the indole analogs do not target the bacterial cell division protein FtsZ as had been hypothesized for totarol.

Increased endothelial cell selectivity of triazole-bridged dihalogenated A-ring analogues of combretastatin A–1

The antiproliferative activity on ovarian cancer (SK-OV-3) cells of a series of triazole-bridged combretastatin analogues (37, 38, 40–43) containing dihalogenation of the A-ring is reported, and compared with their trimethoxy analogues (5, 15, 39). It was found that dihalogenation with either bromine or iodine was a tolerated modification when compared to the parent compound combretastatin (CA–4, 1) and had less effect than B-ring modification on potency. These compounds exhibited G2/M arrest, and maintained antitubulin activity. Further assays on human umbilical vein endothelial cells (HUVECs) demonstrated the potential antivascular effects of these triazoles. Of particular note was a 3,5-diiodo-4-methoxyaryl triazole (43) which had promising 7-fold selectivity for HUVECs over ovarian cancer cells.

Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors

A structure-activity relationship study focusing on the A-ring of vitamin D3 (VD3) was undertaken to elucidate its role in inhibiting the Hedgehog pathway and in mediating anti-cancer effects. Analogues resulting from simple functional group substitution at 3' position of VD3 were evaluated in a variety of biological assays to determine their ability to selectively inhibit Hh signaling. Moderately active Hh inhibitors that have insignificant binding affinity for VDR were identified; however, these compounds also activate the traditional VDR pathway, presumably due to metabolites produced in the cultured cells. Thus, further structural modifications to the VD3 scaffold are required to yield potent, selective Hh inhibitors.

Function oriented synthesis: preparation and initial biological evaluation of new A-ring-modified bryologs

The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7–2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A-ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function.

Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone

The biological activity of two seven-membered A-ring (A-homo) analogues of progesterone was evaluated by transactivation assays in Cos-1 cells and by determination of Bcl-xL expression levels in T47D cells. The results show that both compounds act as selective progesterone receptor (PR) agonists but lack mineralocorticoid receptor (MR) activity. Molecular modelling using semiempirical AM1 and ab initio HF/6-31G∗∗ calculations, showed that the A-ring of the A-homo steroids may adopt five different conformations, although only three correspond to low energy conformers. The low energy conformers of each analogue were introduced into the ligand binding pocket of the PR ligand binding domain (LBD) obtained from the PR LBD–progesterone crystal structure. The steroid binding mode was then analyzed using 10ns of molecular dynamics (MD) simulation. The PR LBD–progesterone complex was also simulated as a control system. The MD results showed that both A-homo steroids have one conformer that may be properly recognized by the PR, in agreement with the observed progestagen activity. Moreover, the simulation revealed the importance of a water molecule in the formation of a hydrogen bonding network among specific receptor residues and the steroid A-ring carbonyl.

Aromatic A-ring analogues of orobanchol, new germination stimulants for seeds of parasitic weeds

Strigolactones are signaling compounds in plants of increasing importance. In this paper the focus is on their activity as germinating agents for seeds of parasitic weeds. The syntheses of aromatic A-ring analogues of the germination stimulant orobanchol have been described. Starting substrate is the ABC unit of the stimulant GR24. Oxidation at the C-4 position gives a 4-oxo derivative which on subsequent reduction produces two C-4 epimeric alcohols, syn and anti in a ratio of 82 : 3. For practical access of the C-4 anti alcohol, the predominant syn epimer is inverted by a Mitsunobu procedure. The anti C-4 alcohol is then coupled with the D-ring in a one-pot two-step process involving a formylation and a reaction with bromobutenolide to give a mixture of the diastereomeric aromatic A-ring analogues of orobanchol. In contrast, the syn C-4 alcohol cannot be coupled directly with the D-ring. Protection of the C-4 syn OH is a prequisite. The best protecting function is the SEM group as deprotection after coupling with the D-ring can then readily be achieved. The structures of these new analogues have been ascertained by X-ray analyses. Both diastereomers of the C-4 syn as well as the C-4 anti orobanchol analogues have been tested as germination agents of seeds of Striga hermonthica and Orobanche ramosa. In addition, the acetates of both epimeric C-4 alcohols have been prepared and tested. Both diastereomers of the 4-oxo derivative have been prepared and bioassayed as well. The bioassays reveal that the diastereomers having the natural relative configuration are most active. The data also suggest that hydrogen bonding is not an important factor in the binding of the stimulant molecules in the receptor.

A new efficient synthesis of GR24 and dimethyl A-ring analogues, germinating agents for seeds of the parasitic weeds Striga and Orobanche spp.

An efficient and high yielding preparation for the synthetic germination stimulant GR24 ( 5) and its A-ring dimethyl-substituted analogues 30– 32 has been described. The first step involves a Stobbe condensation of benzaldehydes 9– 11 with dimethyl succinate. Subsequent transposition of the ester and reduction of the double bond provides the building blocks 15– 17 for an intramolecular Friedel–Crafts acylation. ABC-lactones 22– 25 are prepared from γ-keto esters 18– 21 by saponification, subsequent reduction with sodium borohydride followed by acid-catalyzed lactonization. Coupling of the lactones with the D-ring is accomplished by formylation and subsequent treatment with bromobutenolide 8 to give GR24 and its dimethyl analogues. Bioassays with Striga hermonthica seeds reveal that the dimethyl analogues are slightly less active than GR24 itself.

Antivascular and anticancer activity of dihalogenated A-ring analogues of combretastatin A-4

The generally accepted view is that the 3,4,5-trimethoxy-substituted aromatic A-ring of combretastatin A-4 (CA-4) and its analogues should be conserved in order to maintain biological activity through enforcing an active molecular conformation. Contrary to this, we have found that substituting the larger meta-methoxy groups of CA-4 with smaller halogen atoms results in compounds that are equipotent or more potent than CA-4 itself in vitro.

New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D 3: (2′-hydroxymethyl)tetrahydrofuro[1,2- a]-25-hydroxyvitamin D 3

Conceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2- a]-A-ring phosphine oxides (+)- 4 and (−)- 4 were successfully prepared from methyl 2-pyrone-3-carboxylate and ( S)- or ( R)-2-( tert-butyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectively. In addition, (2′-hydroxymethyl)tetrahydrofuro[1,2- a]-25-hydroxyvitamin D 3 3a and 3b as new A-ring-modified analogs of the natural hormone 1α,25-dihydroxyvitamin D 3 were readily synthesized by using Lythgoe-type coupling of the A-ring phosphine oxides (+)- 4 and (−)- 4 with C,D-ring ketone (+)- 5.

Enantioselective Synthesis and Proteasome Inhibition of A-Ring Analogs of (-)-Epigallocatechin Gallate (EGCG), the Active Ingredient of Green Tea Extract

The A-ring analog compound 8 of(-)-EGCG (1), the active ingredient of green tea, and compound 9, analog of the natural catechin 6 from C. salvifolius, as well as their enantiomers 10 and 11 have been synthesized enantioselectively. They show proteasomal inhibitory activities under cell free conditions, at a potency lower than that of (-)-EGCG. The results suggest that the hydroxyl groups in A-ring of (-)-EGCG play a role in enhancing the activity. The acetylated derivatives of these compounds, 12-15, show cytotoxic activities and proteasomal inhibition after cellular intake, presumably acting as pro-drugs.

First Total Synthesis of Protoapigenone and Its Analogues as Potent Cytotoxic Agents

Protoapigenone (1), isolated from Thelypteris torresiana, previously showed significant cytotoxic activity against five human cancer cell lines. In a continued structure-activity relationship study, the first total synthesis and modification of 1 were achieved. All synthesized compounds and related intermediates were evaluated for cytotoxic activity against five human cancer cell lines, HepG2, Hep3B, MDA-MB-231, MCF-7, and A549. Among them, 24 showed 2.2-14.2-fold greater cytotoxicity than 1 and naphthyl A-ring analogues remarkably enhanced the 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.

Novel A-ring analogs of the hormone 1α,25-dihydroxyvitamin D 3: synthesis and preliminary biological evaluation

Prepared from a commercial prostaglandin building block, novel vitamin D 3 analogs with a contracted five-membered A-ring were designed and synthesized to mimic the A-ring diol structure of the natural hormone 1α,25-dihydroxyvitamin D 3. Prepared from commercial 1,4-cyclohexanedione, a structurally simplified analog was designed and synthesized in which a suitably oriented primary allylic hydroxyl group at the C-2 position might be a surrogate for the biologically important 1α-OH in the natural hormone.

Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin D receptor and its ligands: studies of A-ring modified 19-norvitamin D analogs

To clarify the structure–function relationship (SFR) of vitamin D analogs in terms of their interaction with the vitamin D receptor (VDR), we have proposed a new approach, two-dimensional alanine scanning mutational analysis (2D-ASMA). In this paper, attention was focused on the interactions around the A-ring of vitamin D. For this purpose, we synthesized four new 2-substituted 19-norvitamin D derivatives ( 3– 6). The VDR affinity ( 3– 6: 1, 5, 2 and 1/140, respectively) and transcriptional activity ( 3– 6: 10, 30, 2 and 0.3, respectively) of the four compounds were evaluated relative to 1,25-(OH) 2D 3 ( 5) (normalized to 1). Then, the transcriptional activities of wild-type and 18 mutant VDRs induced by the four compounds ( 3– 6) were investigated. The results of this 18×4 2D-ASMA were presented as a patch table, and the effects of the mutations were analyzed in comparison with the natural hormone ( 1) and 2-methylene-19-nor-20-epi-1,25-(OH) 2D 3 (2MD, 2). Of the four A-ring analogs, the 2α-hydroxyethoxy derivative ( 3) showed striking differences in the pattern on the patch table. From the results, we suggest a docking mode of this compound ( 3) in which the A-ring adopts the α conformation.

Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin D receptor and its ligands: studies of A-ring modified 19-norvitamin D analogs*1, *2

To clarify the structure–function relationship (SFR) of vitamin D analogs in terms of their interaction with the vitamin D receptor (VDR), we have proposed a new approach, two-dimensional alanine scanning mutational analysis (2D-ASMA). In this paper, attention was focused on the interactions around the A-ring of vitamin D. For this purpose, we synthesized four new 2-substituted 19-norvitamin D derivatives ( 3 – 6 ). The VDR affinity ( 3 – 6 : 1, 5, 2 and 1/140, respectively) and transcriptional activity ( 3 – 6 : 10, 30, 2 and 0.3, respectively) of the four compounds were evaluated relative to 1,25-(OH) 2 D 3 ( 5 ) (normalized to 1). Then, the transcriptional activities of wild-type and 18 mutant VDRs induced by the four compounds ( 3 – 6 ) were investigated. The results of this 18×4 2D-ASMA were presented as a patch table, and the effects of the mutations were analyzed in comparison with the natural hormone ( 1 ) and 2-methylene-19-nor-20-epi-1,25-(OH) 2 D 3 (2MD, 2 ). Of the four A-ring analogs, the 2α-hydroxyethoxy derivative ( 3 ) showed striking differences in the pattern on the patch table. From the results, we suggest a docking mode of this compound ( 3 ) in which the A-ring adopts the α conformation.