| 1. |
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| 2. |
- Dahlqvist, Alexander, et al.
(författare)
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Aminopyrimidine-galactose hybrids are highly selective galectin-3 inhibitors
- 2019
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 10:6, s. 913-925
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Tidskriftsartikel (refereegranskat)abstract
- Galectins are a family of carbohydrate recognition proteins involved in, among other things, modulating cell signalling and cell-environment interactions, giving them roles in several pathologies like cancer and idiopathic lung fibrosis. Hence, developing new galectin inhibitors with high affinity and high selectivity is important to be able to target such diseases. Most existing galectin inhibitors have a disaccharide scaffold, but there has been success as of late in developing monogalactoside inhibitors such as α-arylthioglycosides. Here, we report aminopyrimidine-derivatised galactosides as good galectin-3 inhibitors with affinities down to 1.7 μM and a more than 300-fold selectivity over galectin-1. Mutant studies replacing Arg144 in galectin-3 with lysine and serine support the hypothesis that the binding of the derivatives involves interactions with Arg144. Molecular dynamics simulations converged to stable poses of the inhibitor aminopyrimidine moiety with polar interactions with Asp148 and Ser237, while the aryl-aminopyrimidine ring stacked onto the side chain of Arg144. Hence, combining an aminopyrimidine motif with a phenyl α-thiogalactoside motif offers an attractive route towards highly selective galectin-3 inhibitors.
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| 3. |
- Dutta, Suman, et al.
(författare)
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Carba-LNA modified siRNAs targeting HIV-1 TAR region downregulate HIV-1 replication successfully with enhanced potency
- 2011
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 2:3, s. 206-216
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Tidskriftsartikel (refereegranskat)abstract
- The conformationally-locked carbocyclic nucleosides carbaLNA ("jcLNA") (Gagnon et al., Biochemistry, 2010, 49, 10166; Srivastava et al., J. Am. Chem. Soc., 2007, 129, 8362; Xu et al., J. Org. Chem., 2009, 74, 6534; Zhou and Chattopadhyaya, J. Org. Chem., 2010, 75, 2341; Zhou et al., J. Org. Chem., 2009, 74, 118) are chemically engineered by fusing a carbocyclic ring at the C2' to C4' chiral centres in a stereospecific manner at the alpha-face of the pentose-sugar of the native nucleosides. The benefit of the chemically-modified oligonucleotides with the jcLNA scaffold has been shown to be their uniquely enhanced nuclease resistance in the blood serum as well as their improved RNase H recruitment capability to cleave the target RNA in the hybrid antisense-RNA duplex when used as an antisense agent, compared to those of locked nucleic acid (LNA) modified counterparts. Herein we report the relative inhibition efficiency of HIV-1 by jcLNA modified siRNAs targeting TAR region compared to those of the LNA counterparts, in that the former were found to exhibit improved silencing efficiency and displayed enhanced stability in human serum with negligible cytotoxicity compared to those of the latter. A single jcLNA substitution as the 3'-overhang of the guide strand displayed near native-like IC50 value (of 4.01 +/- 0.87 nM compared to the nearly two-fold higher IC50 value of 7.15 +/- 1.57 nM for LNA modified counterparts, and of the native siRNA of 1.84 +/- 0.16 nM) and significantly higher hp value for the stability in serum (11.9 h for jcLNA, 6.8 h for LNA and 3.0 h for native), thereby showing that the efficiency of jcLNA-modified-siRNAs is supported by stability without compromising the native-like efficiency and target RNA recognition and subsequent down-regulation. Amongst all the modified siRNAs so far used to target HIV-1 TAR region, the best IC50 value was obtained for the doubly-modified siRNA in which jcLNA substitution was introduced both at position 1 and 20 of the antisense strand (T-1 + T-20, i.e. jcLNA11 which showed IC50 value of 0.54 +/- 0.14 nM). The IC50 of this doubly-modified siRNA was more than three-fold lower than that of the native and two-fold lower than that of LNA modified counterpart, i.e. LNA12: IC50: 1.13 +/- 0.27 nM. Hence the strategy to chemically modify the native siRNAs by substitution with the jcLNA can be considered as a significant development, leading to both enhanced siRNA efficiency and serum stability over that of the native.
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| 4. |
- Dutta, Suman, et al.
(författare)
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The R-diastereomer of 6 '-O-toluoyl-carba-LNA modification in the core region of siRNA leads to 24-times improved RNA silencing potency against the HIV-1 compared to its S-counterpart
- 2011
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 2:11, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- The modified siRNA with pure [6'(S)-O-(p-toluoyl)-7'(S)-methyl]-carba-LNA [6'(S)-O-toluoyl-jcLNA] at position T(13) displayed an IC(50) of 79.8 nM, which has been found to be nearly 24-times less potent as a HIV-1 RNAi silencing agent against TAR RNA than that of the corresponding pure [6'(R)-O-(ptoluoyl)-7'(S)-methyl]jcLNA [6'(R)-O-(p-toluoyl)-jcLNA] counterpart [IC(50) 3.3 nM]. The later [6'(R)-O-(p-toluoyl)-jcLNAl-modified siRNAs have been found to be nearly 2-fold more efficient as a silencing agent than the corresponding 6'-deoxy-jcLNA modified siRNA [IC(50) 8.1 nM], and also nearly 3-fold more effective as a silencing agent than that of LNA-modified siRNA [IC(50) 11.7 nM], thereby showing that the 6'-carbon center in the jcLNA-modified siRNA in the core region is relatively more exposed to the Ago protein in the RISC with a clear chirality preference for the siRNA cleavage reaction. It is noteworthy that the IC(50) of jcLNA-modified siRNAs are very comparable to that of the native siRNA [1.8 nM]. The jcLNA derivatized siRNAs, however, have a clear advantage of being, in general, considerably more stable in human serum. The main structural difference in duplexes of the antisense strand of the 6'(R or S)-O-(p-toluoyl)-jcLNA modified siRNA and target RNA duplex is found to be the spatial orientation of the 6'(R)-O-toluoyl group, which is exposed towards the edge of the duplex backbone, while the 6'(S) makes the minor groove relatively inaccessible for the Ago protein in the RISC. Clearly, any further C6'-modification in jcLNA-modified siRNAs with any hydrophobic group for tighter binding and cleavage or for cross-linking in the core region should preferably be done in the 6'(R)-stereochemistry.
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| 5. |
- Fritzson, Ingela, et al.
(författare)
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N-Substituted salicylamides as selective malaria parasite dihydroorotate dehydrogenase inhibitors
- 2011
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2511 .- 2040-2503. ; 2:9, s. 895-898
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Tidskriftsartikel (refereegranskat)abstract
- In our continuing program to develop Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors, a series of N-substituted salicylamides were synthesized and their ability to selectively inhibit PfDHODH was examined. The synthetic program was based on 2-hydroxy-N-(2-phenylethyl)benzamide (1) that weakly inhibits both PfDHODH and human DHODH (hDHODH). Structure activity relationships were examined for developing derivatives. Selective PfDHODH inhibitors with improved potency were obtained by introducing a 2,2-diphenylethyl substitution on the salicylamidic nitrogen. Biological activity of the most potent compounds was confirmed on parasite infected cells in vitro.
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| 6. |
- Goldberg, Kristin, et al.
(författare)
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Oxadiazole isomers : all bioisosteres are not created equal
- 2012
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 3:5, s. 600-604
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Tidskriftsartikel (refereegranskat)abstract
- Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compounds were evaluated and found to have significant differences in their various physical and pharmaceutical properties. Experimental and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.
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| 7. |
- Gossas, Thomas, et al.
(författare)
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The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors : characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:2, s. 432-442
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Tidskriftsartikel (refereegranskat)abstract
- The kinetic characteristics of hydroxamate-based inhibitors of matrix metalloproteinase (MMP)-12 were explored using an SPR biosensor-based assay and enzyme inhibition analysis. These high-affinity inhibitors were shown to dissociate very slowly from the enzyme-inhibitor complex while a carboxylate analogue had a much faster dissociation rate, verifying the importance of the hydroxamate group for the slow dissociation. Progress curve enzyme inhibition analysis confirmed that the hydroxamate compounds but not the carboxylate compound acted as time-dependent inhibitors. The slow dissociation excluded steady-state estimation of IC50-values and K-i values but also made K-i values from progress curve analysis unreliable. Although a full characterization of the inhibitors using biosensor analysis was limited by slow dissociation, it provided kinetic and mechanistic information of relevance for MMP drug discovery and avoided some pitfalls of conventional enzyme inhibition assays.
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| 8. |
- Haglund, Caroline, et al.
(författare)
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Identification of an inhibitor of the ubiquitin-proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function
- 2014
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 5:3, s. 376-385
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-proteasome system (UPS) represents one of the most promising therapeutic targets in oncology to emerge in recent years. Here we used a combination of cytotoxic and image-based screening assays to identify a novel UPS inhibitor, designated HRF-3. HRF-3 evokes a gene expression profile similar to that of other characterized ups inhibitors, suggesting a common mechanism of action. Consistent with UPS inhibition, HRF-3 induced strong accumulation of polyubiquitinated proteins in cells. Surprisingly, HRF-3 induced only weak accumulation of two proteasome targeted reporter proteins, Ub(G76V)-YFP and ZsGreen-ODC. Consistent with this observation, HRF-3 did not inhibit proteasome proteolytic activity in an in vitro assay. Similar to a number of other UPS inhibitors, HRF-3 increased the expression of the redox-inducible protein Hmox-1. In distinction to the 20S inhibitor bortezomib, but similarly to two different p97/VCP inhibitors. HRF-3 did not elicit strong induction of the chaperone Hsp70B'. Finally, we show that HRF-3 is cytotoxic to a variety of cancer cell lines and ex vivo patient tumour cells, with the strongest activity observed in cells of leukemic/myeloma origin. Taken together our data show that HRF-3 induces polyubiquitin accumulation in the absence of efficient proteasomal blocking, and suggest that induction of oxidative stress is a common denominator of UPS inhibitors.
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| 9. |
- Kulén, Martina, et al.
(författare)
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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
- 2019
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Ingår i: MedChemComm. - : Royal Society of Chemistry. - 2040-2503 .- 2040-2511. ; 10:11, s. 1966-1987
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Tidskriftsartikel (refereegranskat)abstract
- Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.
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| 10. |
- Lam, V. M., et al.
(författare)
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Discovery of trace amine-associated receptor 1 ligands by molecular docking screening against a homology model
- 2015
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 6:12, s. 2216-2223
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Tidskriftsartikel (refereegranskat)abstract
- Trace Amines (TA) are side-products of the synthesis of classical neurotransmitters within the brain. TAs exert their effect by binding to a family of G protein-coupled receptors termed Trace Amine-Associated Receptors (TAARs). TAAR1 is the best characterised member of this family and studies on TAAR1 have shown that this receptor is a negative regulator of dopamine transmission. Considering the limited number of pharmacological probes available for TAAR1, we aimed to identify novel ligands of this receptor using structure-based virtual screening. A homology model of TAAR1 was generated and over three million commercially available compounds were screened against the orthosteric site using molecular docking. Among the 42 top-ranked compounds that were tested in functional assays, three partial agonists with EC50 values ranging from 1 to 52 mu M were discovered. In addition, four potentially weak antagonists were identified. Ten analogs of the two most potent agonists from the screen were also evaluated and three of these displayed equal or greater activity compared to the parent compound. Several of the discovered ligands represent novel scaffolds and are thus promising starting points for development of new pharmacological tools for studying TAAR1 biology.
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| 11. |
- Lam, V. M., et al.
(författare)
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Discovery of trace amine-associated receptor 1 ligands by molecular docking screening against a homology model
- 2015
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Ingår i: MedChemComm. - 2040-2503 .- 2040-2511. ; 6, s. 2216-2223
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Tidskriftsartikel (refereegranskat)abstract
- Trace Amines (TA) are side-products of the synthesis of classical neurotransmitters within the brain. TAs exert their effect by binding to a family of G protein-coupled receptors termed Trace Amine-Associated Receptors (TAARs). TAAR1 is the best characterised member of this family and studies on TAAR1 have shown that this receptor is a negative regulator of dopamine transmission. Considering the limited number of pharmacological probes available for TAAR1, we aimed to identify novel ligands of this receptor using structure-based virtual screening. A homology model of TAAR1 was generated and over three million commercially available compounds were screened against the orthosteric site using molecular docking. Among the 42 top-ranked compounds that were tested in functional assays, three partial agonists with EC50 values ranging from 1 to 52 [small mu ]M were discovered. In addition, four potentially weak antagonists were identified. Ten analogs of the two most potent agonists from the screen were also evaluated and three of these displayed equal or greater activity compared to the parent compound. Several of the discovered ligands represent novel scaffolds and are thus promising starting points for development of new pharmacological tools for studying TAAR1 biology.
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| 12. |
- Llona-Minguez, Sabin, et al.
(författare)
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Structure-metabolism-relationships in the microsomal clearance of piperazin-1-ylpyridazines
- 2017
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 8:7, s. 1553-1560
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we provide insight into the metabolic profile of a series of piperazin-1-ylpyridazines suffering from rapid in vitro intrinsic clearance in a metabolic stability assay using liver microsomes (e.g. compound 1 MLM/HLM t(1/2) = 2/3 min). Aided by empirical metabolite identification and computational predictive models, we designed the structural modifications required to improve in vitro intrinsic clearance by more than 50-fold (e.g. compound 29 MLM/HLM t(1/2) = 113/105 min).
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| 13. |
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| 14. |
- Meinander, K., et al.
(författare)
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Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity
- 2013
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Ingår i: Medchemcomm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:3, s. 549-553
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Tidskriftsartikel (refereegranskat)abstract
- Pseudopeptides based on the kallikrein-related peptidase 3 (KLK3) activating bicyclic peptide “C-4” comprising hydrocarbon-based disulphide bridge mimetics have been synthesized. After investigating different synthetic approaches, the pseudopeptides were successfully cyclized from two L-allylglycine side chains via an alkene ring-closing metathesis reaction during the peptide synthesis. The alkene-linker was formed in a 1 : 1 E/Z isomer ratio. The resulting pseudopeptides were almost as potent as the parent peptide, increasing the activity of KLK3 over four-fold at 200 μg ml−1 (130–140 μM) concentrations.
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| 15. |
- Nedopekina, DA, et al.
(författare)
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Mitochondria-targeted betulinic and ursolic acid derivatives: synthesis and anticancer activity
- 2017
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 8:10, s. 1934-1945
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Tidskriftsartikel (refereegranskat)abstract
- Conjugation of native triterpenoids, namely, betulinic and ursolic acids, with a lypophilic triphenylphosphonium cation led to the dramatic enhancement, as compared to betulinic acid, of their ability to trigger the mitochondrial apoptosis pathway in various types of cancer cells.
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| 16. |
- Nordqvist, Anneli, et al.
(författare)
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Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
- 2012
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 3:5, s. 620-626
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Tidskriftsartikel (refereegranskat)abstract
- Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.
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| 17. |
- Pippione, Agnese C., et al.
(författare)
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4-Hydroxy-N -[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: A novel inhibitor of the canonical NF-κB cascade
- 2017
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 8:9, s. 1850-1855
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Tidskriftsartikel (refereegranskat)abstract
- The NF-κB signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKKβ inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-κB pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-κB pathway, were found to be inactive in human IKKβ enzyme assays.
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| 18. |
- Plowright, Alleyn T., et al.
(författare)
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Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:1, s. 151-158
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Tidskriftsartikel (refereegranskat)abstract
- A novel series of potent diacylglycerol acyl transferase 1 inhibitors was developed from the clinical candidate AZD3988. Replacement of the phenyl cyclohexyl-ethanoate side chain with substituted oxy-linked side chains to introduce changes in shape and polarity, reduce lipophilicity and mask the hydrogen bond donors with internal hydrogen bond acceptors led to improvements in solubility, unbound clearance and excellent selectivity over the related enzyme acyl-coenzyme A:cholesterol acyltransferase 1. A comparison of the small molecule crystal structures of compound 4 and compound 28 is described. Compounds in this series have good ADMET properties and provide an exposure-dependent decrease in circulating plasma triglyceride levels in a rat oral lipid tolerance test.
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| 19. |
- Poongavanam, Vasanthanathan, et al.
(författare)
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Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors : binding mode insights through magnesium complexation and site-directed mutagenesis studies
- 2018
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Ingår i: MedChemComm. - : ROYAL SOC CHEMISTRY. - 2040-2503 .- 2040-2511. ; 9:3, s. 562-575
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Tidskriftsartikel (refereegranskat)abstract
- Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.
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| 20. |
- Rodriguez, Anna, et al.
(författare)
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New selective A(2A) agonists and A(3) antagonists for human adenosine receptors : synthesis, biological activity and molecular docking studies
- 2015
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 6:6, s. 1178-1185
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Tidskriftsartikel (refereegranskat)abstract
- We report the synthesis and pharmacological characterization of a new series of adenosine derivatives on the four adenosine receptors (ARs). In radioligand binding assays, some of the compounds (1, 4, 6 and (R)-6) display a potent affinity for the A(2A)AR (K-i values < 10 nM) with high A(1)/A(2A) and A(2B)/A(2A) selectivity, moderate for the A(3)AR and low for the A(1)AR. The affinity of the epimeric mixture 6 was similar to that of the corresponding (R)-6 stereoisomer and 10-fold higher than that of the (S)-6 stereoisomer. The phenylethylamino group appears to play a key role on the activity, but introduction of groups of different sizes and electronegativity does not induce a substantial change in affinity for the A(2A)AR. In functional assays, most of the compounds produced similar amounts of cAMP compared to NECA, thus behaving as full A(2A)AR agonists. In addition, compounds 1, 2, 3, 5, (S)-6 and 9 resulted to be good antagonists for A(3)AR with K-B in the 6-14 nM range. Docking studies on the A(2A)AR showed a conserved binding mode consistent with previous A(2A)AR agonist-bound crystal structures, allowing for a rational interpretation of the SAR of this compound series.
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| 21. |
- Ryde, Ulf
(författare)
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A fundamental view of enthalpy-entropy compensation
- 2014
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2511. ; 5:9, s. 1324-1336
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, enthalpy-entropy compensation (EEC) during the association of two molecules is studied by minimising model systems with molecular mechanics (MM) or quantum mechanics (QM), calculating translational, rotational, and vibrational contributions to the enthalpy and entropy with standard statistical-mechanics methods, using the rigid-rotor harmonic-oscillator approach. We start with simple two-atom models, for which dispersion and electrostatics can be studied separately, showing that there is no fundamental difference between dispersion, electrostatics, or even covalent interactions. All three types of interactions give rise to EEC and a saturation of T Delta S as Delta H becomes strongly negative. Next, homologous series of complexes dominated either by dispersion or hydrogen bonds are studied. We see no qualitative difference between results obtained at the MM or QM level, and for all complexes except two very weak, EEC is observed, owing to the loss of translational and rotational entropy, typically counteracted by the vibrational entropy. Within homologous series, linear relations between T Delta S and Delta H with slopes of 0.1-1.7 are obtained with no clear difference between dispersive or hydrogen-bonded systems (but similar to 0.01 for ionic and covalent interactions). These relations often reflect the increasing size of the complexes coming from the translational and rotational entropies, but at least for the hydrogen-bonded complexes, it is significantly enhanced also by the vibrational entropy (which depends on the strength of the interaction). Thus, for homologous series of molecules with repeated interactions studied in vacuum, EEC is a rule. However, if water molecules are added, the relation is blurred and it can be predicted that for a real binding reaction in water solution, both enthalpy-entropy compensation and anti-compensation can be observed, depending on the detailed interaction of the two molecules with water before and after binding, further complicated by dynamic effects.
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| 22. |
- Sauvée, Claire, et al.
(författare)
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The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist
- 2013
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Ingår i: Medchemcomm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:11, s. 1439-1442
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Tidskriftsartikel (refereegranskat)abstract
- Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2- diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the alpha-face, which might explain the high selectivity.
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| 23. |
- Scott, James S., et al.
(författare)
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Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:1, s. 95-100
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Tidskriftsartikel (refereegranskat)abstract
- Improving aqueous solubility is a challenge frequently faced within drug discovery programs. Herein we describe increases in solubility in two sub-series of GPR119 agonists through reduction of lipophilicity together with hydrogen bond acceptor modulation. Small molecule X-ray crystallography was utilised to investigate effects on solid state interactions.
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| 24. |
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| 25. |
- Wallinder, Charlotta, et al.
(författare)
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High affinity rigidified AT(2) receptor ligands with indane scaffolds
- 2019
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Ingår i: MedChemComm. - : ROYAL SOC CHEMISTRY. - 2040-2503 .- 2040-2511. ; 10:12, s. 2146-2160
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Tidskriftsartikel (refereegranskat)abstract
- Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.
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