C3 Side Chain Research Articles

Two substrates, three products: Reactions between ferrocene-carboxaldehyde and dioxaphospholene, characterization and crystal structures of oxygenated C3- and C4-chain-containing ferrocenes

Reactions of aldehydes RCHO with 2,2,2-trimethoxy-4,5-dimethyl-1,3,2-dioxaphospholene are known to form trimethylbiacetyl-aldehyde-phosphite adducts which upon methanolysis gave rise to the corresponding symmetrical 3-R-2,4-pentanediones (R = aryl, alkyl). Reactions between ferrocenecarboxaldehyde and the biacetyl-trimethylphosphite adduct, whatever the experimental conditions used, afforded three new oxygenated C3 and C4 side-chain containing ferrocenyl complexes, namely, 1-ferrocenyl-1,2-propanedione (1, Fc–C(O)C(O)CH3; Fc = (η5-C5H5)Fe(η5-C5H4)), 4-methoxy-4-ferrocenyl-3-hydroxy-3-methyl-2-butanone (2, Fc–CH(OCH3)C(CH3)(OH)C(O)CH3) as a single diastereoisomer, and the ferrocenyl enone 4-ferrocenyl-3-methyl-3-buten-2-one (3, Fc–CHC(CH3)C(O)CH3) with the enone portion adopting the s-trans conformation in the solid state. The compounds readily purified by silica gel packed column chromatography were isolated in 31–44% yields, and their constitution is in agreement with elemental analyses, IR and multinuclear NMR spectroscopy, and electrospray mass spectrometry. Their molecular identity and geometry have been confirmed by single-crystal X-ray diffraction.

Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1

Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure–activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5′-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a–30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1.

FadD3 is an acyl‐CoA synthetase that initiates catabolism of cholesterol rings C and D in actinobacteria

The cholesterol catabolic pathway occurs in most mycolic acid-containing actinobacteria, such as Rhodococcus jostii RHA1, and is critical for Mycobacterium tuberculosis (Mtb) during infection. FadD3 is one of four predicted acyl-CoA synthetases potentially involved in cholesterol catabolism. A ΔfadD3 mutant of RHA1 grew on cholesterol to half the yield of wild-type and accumulated 3aα-H-4α(3'-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP), consistent with the catabolism of half the steroid molecule. This phenotype was rescued by fadD3 of Mtb. Moreover, RHA1 but not ΔfadD3 grew on HIP. Purified FadD3(Mtb) catalysed the ATP-dependent CoA thioesterification of HIP and its hydroxylated analogues, 5α-OH HIP and 1β-OH HIP. The apparent specificity constant (k(cat) /K(m) ) of FadD3(Mtb) for HIP was 7.3 ± 0.3 × 10(5) M(-1) s(-1) , 165 times higher than for 5α-OH HIP, while the apparent K(m) for CoASH was 110 ± 10 μM. In contrast to enzymes involved in the catabolism of rings A and B, FadD3(Mtb) did not detectably transform a metabolite with a partially degraded C17 side-chain. Overall, these results indicate that FadD3 is a HIP-CoA synthetase that initiates catabolism of steroid rings C and D after side-chain degradation is complete. These findings are consistent with the actinobacterial kstR2 regulon encoding ring C/D degradation enzymes.

Synthesis of (1α)‐1,25‐Dihydroxyvitamin D3 with a β‐Positioned Seven‐Carbon Side Chain at C(12)

AbstractA convergent synthesis of an analogue of (1α)‐1,25‐dihydroxyvitamin D3 (1b) with a C7 side chain at C(12), i.e., of 5 (Fig.), is described. A key step of the synthesis is the assembly of the triene system by a PdII‐catalyzed ring closure of an enol triflate (‘bottom’ fragment) followed by coupling of the resulting PdII intermediate with an alkenylboronate (‘upper’ fragment) (Scheme 2). The synthetic strategy allows isotopic labelling at the end of the synthesis.

Completion of the core β-oxidative pathway of benzoic acid biosynthesis in plants

Despite the importance of benzoic acid (BA) as a precursor for a wide array of primary and secondary metabolites, its biosynthesis in plants has not been fully elucidated. BA formation from phenylalanine requires shortening of the C(3) side chain by two carbon units, which can occur by a non-β-oxidative route and/or a β-oxidative pathway analogous to the catabolism of fatty acids. Enzymes responsible for the first and last reactions of the core BA β-oxidative pathway (cinnamic acid → cinnamoyl-CoA → 3-hydroxy-3-phenylpropanoyl-CoA → 3-oxo-3-phenylpropanoyl-CoA → BA-CoA) have previously been characterized in petunia, a plant with flowers rich in phenylpropanoid/benzenoid volatile compounds. Using a functional genomics approach, we have identified a petunia gene encoding cinnamoyl-CoA hydratase-dehydrogenase (PhCHD), a bifunctional peroxisomal enzyme responsible for two consecutively occurring unexplored intermediate steps in the core BA β-oxidative pathway. PhCHD spatially, developmentally, and temporally coexpresses with known genes in the BA β-oxidative pathway, and correlates with emission of benzenoid volatiles. Kinetic analysis of recombinant PhCHD revealed it most efficiently converts cinnamoyl-CoA to 3-oxo-3-phenylpropanoyl-CoA, thus forming the substrate for the final step in the pathway. Down-regulation of PhCHD expression in petunia flowers resulted in reduced CHD enzyme activity, as well as decreased formation of BA-CoA, BA and their derived volatiles. Moreover, transgenic lines accumulated the PhCHD substrate cinnamoyl-CoA and the upstream pathway intermediate cinnamic acid. Discovery of PhCHD completes the elucidation of the core BA β-oxidative route in plants, and together with the previously characterized CoA-ligase and thiolase enzymes, provides evidence that the whole pathway occurs in peroxisomes.

Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: The hydrophobic side chain influences type A subtype selectivity

Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A series of influenza neuraminidase inhibitors with the pyrrolidinobenzoic acid scaffold containing lipophilic side chains at the C3 position have been synthesized and evaluated for influenza neuraminidase inhibitory activity. The size and geometry of the C3 side chains have been modified in order to investigate structure–activity relationships. The results indicated that size and geometry of the C3-side chain are important for selectivity of inhibition against N1 versus N2 NA, important type A influenza variants that infect man, including the highly lethal avian influenza.

Thermal properties and crystallization behaviors of medium-chain-length poly(3-hydroxyalkanoate)s

Medium-chain-length poly(3-hydroxyalkanoate)s (mcl-P(3HA)s) with different side-chain length ranging from C3–C9 were synthesized from 2-alkenoic acids of C6–C12 by using a metabolically engineered strain of Escherichia coli. The effect of side-chain length of mcl-P(3HA)s on thermal properties and crystallization behaviors was investigated by DSC and X-ray analyses. All mcl-P(3HA)s formed a chain-packed crystalline structure in the solvent-cast films. Melting temperatures of solvent-cast film of mcl-P(3HA)s first decreased from 59 °C to 45 °C with the change of side-chain from C3 to C4 and thereafter increased to 69 °C with an extension of side-chain to C9. The X-ray diffraction patterns indicate the formation of a layered structure aligned the main-chains in planes involving side-by-side packing of side-chains with a periodic distance of 1.6–2.8 nm for the mcl-P(3HA)s with over C4 side-chain. The interlayer distance increased proportionally to the length of side-chain for the mcl-P(3HA)s with over C4 side-chain, while the corresponding value of mcl-P(3HA) with C3 side-chain was apparently deviated from the extrapolated line plotted the distance against side-chain length. These results indicate that the changeover in crystallization manner occurs between P(3HA)s with under C3 side-chain and with over C4 side-chain. For the mcl-P(3HA)s with side-chain carbon number over C7, two distinct phase transitions were happened during heating process from a melt-quenched amorphous state. At lower temperature region, the mcl-P(3HA) molecules formed a smectic liquid-crystalline structure owing to the side-chain interactions, and the structure was disrupted at temperatures between 20 and 50 °C. After the disruption of smectic aggregates, the crystallization of mcl-P(3HA) chains immediately occurred with participation of both main- and side-chains.

Rac-[3-Hydroxy-6,9-dimethyl-6-(4-methylpent-3-en-1-yl)-6a,7,8,9,10,10a-hexahydro-6H-1,9-epoxybenzo[c]chromen-4-yl](phenyl)methanone

The title compound congestiflorone, C28H32O4, which was isolated from the stem bark of Mesua congestiflora, consists of a benzophenone skeleton with two attached pyran rings to which a cyclo­hexane ring and a C6 side chain are bonded. The benzene ring is significantly distorted from planarity (r.m.s. deviation = 0.0007 Å) due to the constraints imposed by junctions with the two pyran rings. The cyclo­hexane ring is in a chair conformation, one pyran ring is in a boat conformation, while the other is a distorted chair. The phenyl and benzene rings make a dihedral angle of 55.85 (9)°. An intra­molecular O—H⋯O hydrogen bond is observed. In the crystal, mol­ecules are linked via C—H⋯O inter­actions.

Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain

Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography.

Cytotoxic Dehydromonacolins from Red Yeast Rice

Two new dehydromonacolins (1 and 3), together with nine known monacolins (4-12), were isolated from red yeast rice. Compounds 4-6 were isolated from a natural resource for the first time. Their structures were elucidated by means of NMR and mass spectroscopic analyses. The structure of dehydromonacolin N (1) was further confirmed by its semisynthesis from monacolin K (lovastatin) (11). Dehydromonacolin J (2), an intermediate in the semisynthesis of 1, was obtained as a new dehydromonacolin. The structure of dehydromonacolin L (3) was also confirmed by an elimination reaction of monacolin L (12). Compound 1, possessing a C2 side chain, is unprecedented in the natural monacolin family and exhibited moderate cytotoxic activity against Hep G2, Caco-2, and MCF-7 cancer cell lines. Dehydromonacolin K (8) demonstrated the most potent cytotoxicity to all three of these cell lines. The structure-activity relationship of natural and synthesized monacolins was discussed. This is the first report on the cytotoxic effects of dehydromonacolins.

Design, synthesis and evaluation of polar head group containing 2-keto-oxazole inhibitors of FAAH

2-α-Keto oxazoles containing polar head groups in their C5-side chains were designed as fatty acid amide hydrolase (FAAH) inhibitors. Variation in the spacer length resulted in submicromolar α-keto-oxazole FAAH inhibitor (IC50=436nM) presenting electrostatic stabilizing interactions between its polar head group contained in the C5-side chain and the hydrophilic pocket of the enzyme.

A Copolymer of Benzodithiophene with TIPS Side Chains for Enhanced Photovoltaic Performance

A new conjugated copolymer PBDTTT-TIPS containing thiazolothiazole acceptor unit and triisopropylsilylethynyl (TIPS)-functionalized benzodithiophene donor unit was synthesized by Pd-catalyzed Stille coupling and compared with its alkoxy-substituted analogue PBDTTT-C12. PBDTTT-TIPS exhibits decomposition temperature of 377 °C, absorption maximum of 598 nm, HOMO level of −5.3 eV, and hole mobility as high as 1.2 × 10–3 cm2 V–1 s–1. Without any post-treatments, polymer solar cells based on the blend of PBDTTT-TIPS and PC71BM exhibited power conversion efficiency as high as 4.33%, which is 2 times that for device based on the PBDTTT-C12:PC71BM blend. TIPS and C12 side chains exhibit a little impact on absorption, HOMO level, and hole mobility of the polymers, but they significantly influence blend film morphology and photovoltaic performance. TIPS side chains induces excellent compatibility between PBDTTT-TIPS and PC71BM, and the PBDTTT-TIPS:PC71BM blend exhibits perfect phase separation scales around 10–20 nm, which is beneficial to charge separation and enhanced efficiency of the device, while C12 side chains leads to large phase separation, which is responsible for the lower efficiency.

Monoamine oxidase inhibition by C4-substituted phthalonitriles

It was recently reported that a series of C5-substituted phthalimides are remarkably potent reversible inhibitors of recombinant human monoamine oxidase (MAO) B. Modeling studies suggested that the phthalimide ring forms numerous polar interactions with the polar region of the MAO-B substrate cavity while the C5 side chain extends to, and interacts via Van der Waals interactions with the hydrophobic regions of the enzyme entrance cavity. Interactions with both cavities appear to be requirements for high affinity binding. In the present study we have examined an analogs series of C4-substituted phthalonitriles as potential human MAO inhibitors. The phthalonitriles were found to be highly potent reversible MAO-B inhibitors with most analogs exhibiting IC50 values in the low nM range. The phthalonitriles also interacted with human MAO-A, although with lower binding affinities compared to MAO-B. Modeling studies suggest that the high binding affinities of the phthalonitriles to MAO-B may depend, at least in part, on the formation of polar interactions between the nitrile functional groups and the enzyme substrate cavity. Examination of a homologs series of benzonitriles established that the phthalonitrile moiety is more optimal for MAO-B inhibition than the corresponding benzonitrile moiety, and that C3-substituted benzonitriles are better MAO-B inhibitors than C4-substituted benzonitriles. Since elimination of the nitrile functional group yielded compounds with only moderate MAO-B inhibition potencies, it may be concluded that this functional group is privileged for MAO-B inhibition.

Total Synthesis of Optically Active Lycopladine A by Utilizing Diastereoselective Protection of Carbonyl Group in a 1,3-Cyclohexanedione Derivative

We successfully synthesized two enantiomers of bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal 2a, which we first synthesized from the symmetrical diketone 1a via diastereoselective carbon-oxygen bond formation between one of the carbonyl groups and the chiral alcohol on the C2 side chain in a 2,2-disubstituted 1,3-cycloalkanedione derivative. We also report the total synthesis of natural (+)-lycopladine A [(+)-6] from (7R,7aR)-9 and the formal synthesis of unnatural (-)-lycopladine A [(-)-6] from (7S,7aS)-9.

Synthesis and Antibacterial Activities of Pleuromutilin Derivatives with Thiazole-5-Carboxamide and Thioether Moiety

Seven novel pleuromutilin derivatives with thiazole-5-carboxamide and thioether moiety in the C14 side chain were designed and synthesised. The antibacterial activities of the target compounds were tested via agar-well diffusion method in vitro. The results showed that three target compounds still had antibacterial activity against Staphylococcus aureus ATCC26112 and Staphylococcus aureus SC at a low concentration of 0.05 μg mL−1.

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

The development of the coxib family has represented a stimulating approach in the treatment of inflammatory disorders, such as arthritis, and for the management of acute pains, in relation to the well-known traditional Non-Steroidal Anti-inflammatory Drugs (t-NSAIDs). Prompted by the pursuit for new cyclooxygenase-2 (COX-2) inhibitors, endowed with fine tuned selectivity and high potency, in the past years we have identified novel classes of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole scaffold as potentially powerful anti-inflammatory molecules (12-66). All compounds proved to exert an in vitro inhibition profile as good as that shown by reference compounds. Compounds bearing a p-methylsulfonylphenyl substituent at C5 displayed the best issues. In particular, ester derivatives proved to perform the best in vitro profile in terms of selectivity and activity toward COX-2. The cell-based assay data showed that an increase of hindrance at the C3 side chain of compounds could translate to activity enhancement. The human whole blood (HWB) test let to highlight that submitted compounds displayed 5-10 fold higher selectivity for COX-2 vs COX-1 which should translate clinically to an acceptable gastrointestinal safety and mitigate the cardiovascular effects highlighted by highly selective COX-2 inhibitors. Finally, to assess in vivo anti-inflammatory and analgesic activity three different tests (rat paw pressure, rat paw oedema and abdominal constriction) were performed. Results showed good in vivo anti-inflammatory and analgesic activities. The issues gained with these classes of compounds represent, nowadays, a potent stimulus for a further enlargement of the NSAIDs family. In this review we describe the results obtained by our research group on this topic.

Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold

Synthetic compounds with a tri- and tetra-substituted imidazole scaffold are known as selective inhibitors of the p38 mitogen-activated protein (MAP) kinase responsible for proinflammatory cytokine release. The scope is to review the literature describing their design, synthesis and activity studies. To date a great plethora of crystal structures of p38 in complex with small organic ligands have been published. Cocrystallized ligand information is of particular interest to our review study, i.e. ATP itself, the reference inhibitor SB203580 with its aryl-pyridinyl-imidazoles and related imidazole and pyrimidine-based derivatives. The selective inhibitors bind to the pocket of adenosine 5'-triphoshate (ATP) replacing the latter. The hydrophobic region II, however, is not occupied by the natural binder ATP, but accommodates the pyridine substituents preserving the 4-fluorophenyl ring occupation in pocket I as a prerequisite to gain higher binding selectivity and potency than the reference compound SB203580 (4-[5-(4-fluoro-phenyl)-2-(4-methanesulfinyl-phenyl)-3himidazol-4-yl]-pyridine). Experimental and computed work is reviewed which evidence that the 2 position of the pyrimidine ring is amenable to the introduction of a side chain and the replacement of pyridine in SB203580 by a pyrimidine ring improves both inhibitory activity and selectivity for p38 over other kinases. All ligands with a pyridyl C2 side chain occupy the hydrophobic pocket II and in some cases a double hydrogen bond is reported between methionine 109 and glycine 110 of the hinge region, following an observed backbone shift. The substituted pyridine ring binds stronger than the two other side chains on the imidazole scaffold.

Characterization of p-hydroxybenzaldehyde dehydrogenase, the final enzyme of p-hydroxybenzoic acid biosynthesis in hairy roots of Daucus carota

Hairy root cultures of Daucus carota respond to methyl-jasmonate treatment with enhanced accumulation of p-hydroxybenzoic acid. The final C1-side chain of this compound is shaped by p-hydroxybenzaldehyde dehydrogenase (HBD) that catalyzes the formation of p-hydroxybenzoic acid from p-hydroxybenzaldehyde in the presence of NAD+. HBD was biochemically characterized from cell-free hairy root extracts of D. carota. The preferred substrate for HBD was p-hydroxybenzaldehyde. The apparent Km values were 54.8 and 74.4 μM for p-hydroxybenzaldehyde and NAD+, respectively. Divalent metal cations did not significantly affect enzyme activity.

Antidotes to anthrax lethal factor intoxication. Part 2: Structural modifications leading to improved in vivo efficacy

New anthrax lethal factor inhibitors (LFIs) were designed based upon previously identified potent inhibitors 1a and 2. Combining the new core structures with modifications to the C2-side chain yielded analogs with improved efficacy in the rat lethal toxin model.

Synthesis and Antibacterial Activities of Pleuromutilin Derivatives with Quinazolinone and Thioether Groups

Ten novel pleuromutilin derivatives with quinazolinone and thioether groups in the C14 side chain have been designed and synthesised. The antibacterial activities of the target compounds were tested via the agar-well diffusion method in vitro in the concentration of 5.0 μg mL−1 The results showed that all target compounds had displayed obvious antibacterial activity against Staphylococcus aureus ATCC26112 and Staphylococcus aureus SC.