Pivotal Role of an Aliphatic Side Chain in the Development of an HDM2 Inhibitor.
Ontology highlight
ABSTRACT:
SUBMITTER: Ma Y
PROVIDER: S-EPMC4027732 | biostudies-literature | 2014 May
REPOSITORIES: biostudies-literature
Publications
Pivotal Role of an Aliphatic Side Chain in the Development of an HDM2 Inhibitor.
Ma Yao Y Lahue Brian R BR Gibeau Craig R CR Shipps Gerald W GW Bogen Stéphane L SL Wang Yaolin Y Guo Zhuyan Z Guzi Timothy J TJ
ACS medicinal chemistry letters 20140224 5
Introduction of an aliphatic side chain to a key position of a novel piperidine-based HDM2 inhibitor scaffold resulted in significant potency gains, enabling further series progression. ...[more]
Similar Datasets
Project description:The influence of cholesterol's alkyl side chain on membrane properties was studied using a series of synthetic cholesterol derivatives without a side chain or with a branched side chain consisting of 5 to 14 carbon atoms. Cholesterol's side chain is crucial for all membrane properties investigated and therefore essential for the membrane properties of eukaryotic cells.
| S-EPMC4011182 | biostudies-other
Project description:Daphnane diterpenoids were recognized for their extensive range of potent biological activities. In the present study, phytochemical investigation including LC-MS/MS analysis resulted in the identification of five daphnane diterpenoid orthoesters (1-5). Among the five daphnane diterpenoids, two previously unreported compounds, daphnepedunins I and J (2 and 4) were isolated from Daphne pedunculata. The structure of new compounds was elucidated with extensive physicochemical and spectroscopic analyses. Their structure was characterized by the presence of an unusual odd-numbered aliphatic chain connected to an orthoester. The isolated compounds were evaluated for their anti-HIV activity against HIV-1 infection of MT4 cells, and the results indicated that compound 1 showed the most potent anti-HIV activity with an IC50 value of 0.82 nM.
| S-EPMC11365762 | biostudies-literature
Project description:The basic differences between the 20 natural amino acid residues are due to differences in their side-chain structures. This characteristic design of protein building blocks implies that side-chain-side-chain interactions play an important, even dominant role in 3D-structural realization of amino acid codes. Here we present the results of a comparative analysis of the contributions of side-chain-side-chain (s-s) and side-chain-backbone (s-b) interactions to the stabilization of folded protein structures within the framework of the CHARMm molecular data model. Contrary to intuition, our results suggest that side-chain-backbone interactions play the major role in side-chain packing, in stabilizing the folded structures, and in differentiating the folded structures from the unfolded or misfolded structures, while the interactions between side chains have a secondary effect. An additional analysis of electrostatic energies suggests that combinatorial dominance of the interactions between opposite charges makes the electrostatic interactions act as an unspecific folding force that stabilizes not only native structure, but also compact random conformations. This observation is in agreement with experimental findings that, in the denatured state, the charge-charge interactions stabilize more compact conformations. Taking advantage of the dominant role of side-chain-backbone interactions in side-chain packing to reduce the combinatorial problem, we developed a new algorithm, ChiRotor, for rapid prediction of side-chain conformations. We present the results of a validation study of the method based on a set of high resolution X-ray structures.
| S-EPMC2203320 | biostudies-literature
Project description:The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products.
| S-EPMC7794379 | biostudies-literature
Project description:The integrin ?E known as CD103 binds integrin ?7 to form the complete heterodimeric integrin molecule ?E?7. CD103 is mainly expressed by lymphocytes within epithelial tissues of intestine, lung, and skin as well as subsets of mucosal and dermal conventional dendritic cells (cDCs). CD103 has been originally implicated in the attachment of lymphocytes to epithelium in the gut and skin through the interaction with E-cadherin expressed on intestinal epithelial cells, keratinocytes, and Langerhans cells (LCs). However, an impact of CD103 on the cutaneous immune responses and the development of inflammatory skin diseases remains elusive. Here, we report that CD103 regulates the development of psoriasiform dermatitis through the control of the function of cDCs. Deficiency in CD103 exacerbates psoriasiform dermatitis, accompanied by excessive epidermal hyperplasia and infiltration of inflammatory leukocytes. Furthermore, deficiency in CD103 not only accelerates the production of proinflammatory cytokines in psoriatic lesions but also promotes the generation of lymphocytes producing interleukin (IL)-17 in the skin-draining peripheral lymph nodes (PLNs). Under the deficiency in CD103, cDCs localized in PLNs enhance cytokine production following activation. Thus, our findings reveal a pivotal role for CD103 in the control of the function of cDCs to regulate cutaneous inflammation in psoriasiform dermatitis.
| S-EPMC7239860 | biostudies-literature
Project description:The rate with which labile backbone hydrogen atoms in proteins exchange with the solvent has long been used to probe protein interactions in aqueous solutions. Arginine, an essential amino acid found in many interaction interfaces, is capable of an impressive range of interactions via its guanidinium group. The hydrogen exchange rate of the guanidinium hydrogens therefore becomes an important measure to quantify side-chain interactions. Herein we present an NMR method to quantify the hydrogen exchange rates of arginine side-chain 1 Hϵ protons and thus present a method to gauge the strength of arginine side-chain interactions. The method employs 13 C-detection and the one-bond deuterium isotope shift observed for 15 Nϵ to generate two exchanging species in 1 H2 O/2 H2 O mixtures. An application to the protein T4 Lysozyme is shown, where protection factors calculated from the obtained exchange rates correlate well with the interactions observed in the crystal structure. The methodology presented provides an important step towards characterising interactions of arginine side-chains in enzymes, in phase separation, and in protein interaction interfaces in general.
| S-EPMC6391956 | biostudies-literature
Project description:Fatty acid-derivative prodrugs have been utilized extensively to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of active pharmaceutical ingredients. However, to our knowledge, the crystallization behavior of prodrugs modified with different fatty acids has not been explored. In the present work, a series of paliperidone aliphatic prodrugs with alkyl chain lengths ranging from C4 to C16 was investigated with respect to crystal structure, crystal morphology and crystallization kinetics. The paliperidone derivatives exhibited isostructural crystal packing, despite the different alkyl chain lengths, and crystallized with the dominant (100) face in both melt and solution. The rate of crystallization for paliperidone derivatives in the melt increases with alkyl chain length owing to greater molecular mobility. In contrast, the longer chains prolong the nucleation induction time and reduce the crystal growth kinetics in solution. The results show a correlation between difficulty of nucleation in solution and the interfacial energy. This work provides insight into the crystallization behavior of paliperidone aliphatic prodrugs and reveals that the role of alkyl chain length in the crystallization behavior has a strong dependence on the crystallization method.
| S-EPMC10833388 | biostudies-literature
Project description:Biodegradable polyethylene mimics have been synthesized by the introduction of pyrophosphate groups into the polymer backbone, allowing not only hydrolysis of the backbone but also further degradation by microorganisms. Because of cost, low weight, and good mechanical properties, the use of polyolefins has increased significantly in the past decades and has created many challenges in terms of disposal and their environmental impact. The durability and resistance to degradation make polyethylene difficult or impossible for nature to assimilate, thus making the degradability of polyolefins an essential topic of research. The biodegradable polypyrophosphate was prepared via acyclic diene metathesis polymerization of a diene monomer. The monomer is accessible via a three-step synthesis, in which the pyrophosphate was formed in the last step by DCC coupling of two phosphoric acid derivatives. This is the first report of a pyrophosphate group localized in an organic polymer backbone. The polypyrophosphate was characterized in detail by NMR spectroscopy, size exclusion chromatography, FTIR spectroscopy, differential scanning calorimetry, and thermogravimetry. X-ray diffraction was used to compare the crystallization structure in comparison to analogous polyphosphates showing poly(ethylene)-like structures. In spite of their hydrophobicity and water insolubility, the pyrophosphate groups exhibited fast hydrolysis, resulting in polymer degradation when films were immersed in water. Additionally, the hydrolyzed fragments were further biodegraded by microorganisms, rendering these PE mimics potential candidates for fast release of hydrophobic cargo, for example, in drug delivery applications.
| S-EPMC6728087 | biostudies-literature
Project description:The intrinsic conformational biases of individual amino acids and their interstrand side-chain-side-chain (SC-SC) interactions both contribute to the stability of beta-sheets. The relative magnitudes of these effects have been difficult to assess in the context of folded proteins, where tertiary contacts complicate the quantitative analysis of local effects. We now report the results of such an analysis in a much simpler system, a short, stabilized beta-hairpin structure where intrastrand (conformational) and interstrand (SC-SC) influences can be distinguished in the absence of competing protein tertiary interactions. A comprehensive comparison of all pairwise combinations of 11 N-terminal and 7 C-terminal amino acids within an 8-residue, @-tide-stabilized [in which @ denotes the 1,2-dihydro-3(6H)-pyridinyl unit] beta-hairpin reveals distinct differences between the various pairings and shows that the intrastrand and interstrand effects are of comparable magnitude in contributing to the stability of the folded forms over the unfolded forms.
| S-EPMC1202387 | biostudies-literature
Project description:Background: Analysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CO), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX.Methods: Fifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. Serum sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two potential determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay.Results: Tolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Cross-reactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 94.6%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B.Conclusions: Cross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients.
| S-EPMC7716594 | biostudies-literature