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Abstract We describe for the first time the synthesis of biocompatible TiO2 nanoparticles containing a functional NH2 group which are easily dispersible in water. The synthesis of water dispersible TiO2 nanoparticles coated with mercaptosuccinic acid is also reported. We show that it is possible to exchange the stearic acid from pre-synthesised fatty acid-coated anatase 5-nm nanoparticles with a range of organic ligands with no change in the size or morphology. With further organic functionalisation, these nanoparticles could be used for medical imaging or to carry cytotoxic radionuclides for radioimmunotherapy where ultrasmall nanoparticles will be essential for rapid renal clearance.

The present study details the design, synthesis, and bio-evaluation of indoles 3-16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3-16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI 50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7, 12 , and 16 , on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids' 12- and 16 -binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8-16 , highlighting their potential as therapeutic agents with reduced toxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Al-Wahaibi, Abou-Zied, Abdelrahman, Morcoss, Trembleau, Youssif and Bräse.)

A new series of indole-2-carboxamides 5a-g , 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c , 5d , 5f , 5 g , 6e , and 6f have the highest antiproliferative activity with GI 50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI 50 = 33 nM). Compounds 5d , 5f , and 5 g inhibited EGFR WT with IC 50 values ranging from 68 to 85 nM while the GI 50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFR T790M with IC 50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC 50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFR WT and EGFR T790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.

A small set of indole-based derivatives, IV and Va - I , was designed and synthesized. Compounds Va - i demonstrated promising antiproliferative activity, with GI 50 values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives- Va , Ve , Vf , Vg , and Vh -were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC 50 value of 71 ± 06 nM, which is higher than the reference erlotinib (IC 50 = 80 ± 05 nM). Compounds Va , Ve , Vf , Vg , and Vh were further tested for BRAF V600E inhibitory activity. The tested compounds inhibited BRAF V600E with IC 50 values ranging from 77 nM to 107 nM compared to erlotinib's IC 50 value of 60 nM. The inhibitory activity of compounds Va , Ve , Vf , Vg , and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAF V600E , and VEGFR-2.

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four cancer cell lines tested, with mean GI 50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI 50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI 50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC 50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC 50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC 50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a-e , 4a-c and pyrrolo[3,4- b ]indol-3-ones 5a-c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of 3a-e , 4a-c , and 5a-c revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds 3a-e , 4a-c , and 5a-c had significant antiproliferative activity with GI 50 values ranging from 29 nM to 78 nM, with 3a-e outperforming 4a-c and 5a-c in their inhibitory actions against the tested cancer cell lines. Compounds 3a-e were tested for EGFR inhibition, with IC 50 values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m -piperidinyl derivative 3e (R = m -piperidin-1-yl), with an IC 50 value of 68 nM, which was 1.2-fold more potent than erlotinib (IC 50 = 80 nM). Interestingly, all the tested compounds 3a-e had higher anti-BRAF V600E activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward EGFR T790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAF V600E and EGFR T790M enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a-e revealed safety and good pharmacokinetic profile.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria., (© 2022. The Author(s).)

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa - j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a - k , 6a - c , and 7 . Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a - k , 6a - c , and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a - k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a - c and 7 , indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI 50 = 1.10 µM), compounds 5d , 5e , 5h , 5i , 5j , and 5k were the most effective of the synthesised derivatives, with GI 50 ranging from 0.95 µM to 1.50 µM. Compounds 5d , 5e , 5h , 5i , 5j , and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53.

Mycobacterium tuberculosis ketol-acid reductoisomerases have been widely studied due to their metabolic importance towards development of drug-resistant bacteria treatment. We here report the biochemical characterization of a new KARI (MtKARI-II) from a Mycobacterium tuberculosis variant with a similar kinetic profile to class I KARIs. Phylogenetic analysis suggested that MtKARI-II is clustered into a class II KARI superfamily., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13-22 have been developed as dual EGFR and BRAF V600E inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19-22 demonstrating potent antiproliferative activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAF V600E . Compounds 15, and 19-22 exhibited inhibitions of EGFR with IC 50 ranging from 32 nM to 63 nM which were superior to erlotinib (IC 50  = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of BRAF V600E (IC 50  = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI 50  = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and BRAF V600E active sites to clarify their binding modes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC 50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 μM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 μM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 M pro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 M pro with an IC 50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-M pro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-M pro inhibitors that are worth being further optimized and developed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19-31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC 50 values: 0.82-1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC 50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC 50  = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17-19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAF V600E and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAF V600E , a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their antiproliferative activity against a panel of four human cancer cell lines. Compounds 20-23, 28-31, and 33 showed promising antiproliferative activities. These compounds were further tested for their inhibitory potencies against EGFR and BRAF V600E kinases with erlotinib as a reference drug. Compounds 23 and 33 exhibited equipotency to doxorubicin against the four cell lines and efficiently inhibited both EGFR (IC 50  = 0.08 and 0.09 µM, respectively) and BRAF V600E (IC 50  = 0.1 and 0.29 µM, respectively). In cell cycle study of MCF-7 cell line, compounds 23 and 33 induced apoptosis and exhibited cell cycle arrest in both Pre-G1 and G2/M phases. Molecular docking analyses revealed that the new compounds can fit snugly into the active sites of EGFR, and BRAF V600E kinases. Compound 23, 31 and 33 adopted similar binding orientations and interactions to those of erlotinib and vemurafenib., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The discovery of liquid water at several locations in the solar system raises the possibility that microbial life may have evolved outside Earth and as such could be accidently introduced into the Earth's ecosystem. Unusual sugars or amino acids, like non-proteinogenic isovaline and α-aminoisobutyric acid that are vanishingly rare or absent from life forms on Earth, have been found in high abundance on non-terrestrial carbonaceous meteorites. It is therefore conceivable that exo-microorganisms might contain proteins that include these rare amino acids. We therefore asked whether the mammalian immune system would be able to recognize and induce appropriate immune responses to putative proteinaceous antigens that include these rare amino acids. To address this, we synthesised peptide antigens based on a backbone of ovalbumin and introduced isovaline and α-aminoisobutyric acid residues and demonstrated that these peptides can promote naïve OT-I cell activation and proliferation, but did so less efficiently than the canonical peptides. This is relevant to the biosecurity of missions that may retrieve samples from exoplanets and moons that have conditions that may be permissive for life, suggesting that accidental contamination and exposure to exo-microorganisms with such distinct proteomes might pose an immunological challenge.

As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein-protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide.

Tricyclic carbazole is an important scaffold in many naturally occurring metabolites, as well as valuable building blocks. Here we report the reconstitution of the ring A formation of the bacterial neocarazostatin A carbazole metabolite. We provide evidence of the involvement of two unusual aromatic polyketide proteins. This finding suggests how new enzymatic activities can be recruited to specific pathways to expand biosynthetic capacities. Finally, we leveraged our bioinformatics survey to identify the untapped capacity of carbazole biosynthesis.

We describe the syntheses and crystal structures of two indole derivatives, namely a second monoclinic polymorph of ethyl 5-chloro-1H-indole-2-carboxyl-ate C11H10ClNO2, (I), and ethyl 5-chloro-3-iodo-1H-indole-2-carboxyl-ate, C11H9ClINO2, (II). In their crystal structures, both compounds form inversion dimers linked by pairs of N-H⋯O hydrogen bonds, which generate R 2 (2)(10) loops. The dimers are linked into double chains in (I) and sheets in (II) by a variety of weak inter-actions, including π-π stacking, C-I⋯π, C-Cl-π inter-actions and I⋯Cl halogen bonds.

We describe the syntheses and crystal structures of two indole derivatives, namely 6-isopropyl-3-(2-nitro-1-phenyl-eth-yl)-1H-indole, C19H20N2O2, (I), and 2-(4-meth-oxy-phen-yl)-3-(2-nitro-1-phenyl-eth-yl)-1H-indole, C23H20N2O3, (II); the latter crystallizes with two mol-ecules (A and B) with similar conformations (r.m.s. overlay fit = 0.139 Å) in the asymmetric unit. Despite the presence of O atoms as potential acceptors for classical hydrogen bonds, the dominant inter-molecular inter-action in each crystal is an N-H⋯π bond, which generates chains in (I) and A+A and B+B inversion dimers in (II). A different aromatic ring acts as the acceptor in each case. The packing is consolidated by C-H⋯π inter-actions in each case but aromatic π-π stacking inter-actions are absent.

We describe the crystal structures of four indole derivatives with a phenyl ring at the 2-position and different carbonyl-linked substituents at the 3-position, namely 1-(2-phenyl-1H-indol-3-yl)ethanone, C16H13NO, (I), 2-cyclo-hexyl-1-(2-phenyl-1H-indol-3-yl)ethanone, C22H23NO, (II), 3,3-dimethyl-1-(2-phenyl-1H-indol-3-yl)butan-1-one, C20H21NO, (III), and 3-benzoyl-2-phenyl-1H-indole, C21H15NO, (IV). In each case, the carbonyl-group O atom lies close to the indole-ring plane and points towards the benzene ring. The dihedral angles between the indole ring system and 2-phenyl ring for these structures are clustered in a narrow range around 65°. The dominant inter-molecular inter-action in each case is an N-H⋯O hydrogen bond, which generates a C(6) chain, although each structure possesses a different crystal symmetry. The C(6) chains are consolidated by different (C-H⋯O, C-H⋯π and π-π stacking) weak inter-actions, with little consistency between the structures.

The crystal structures of four indole derivatives with various substituents at the 2-, 3- and 5-positions of the ring system are described, namely, ethyl 3-(5-chloro-2-phenyl-1H-indol-3-yl)-3-phenyl-propano-ate, C25H22ClNO2, (I), 2-bromo-3-(2-nitro-1-phenyl-eth-yl)-1H-indole, C16H13BrN2O2, (II), 5-meth-oxy-3-(2-nitro-1-phenyl-eth-yl)-2-phenyl-1H-indole, C23H20N2O3, (III), and 5-chloro-3-(2-nitro-1-phenyl-eth-yl)-2-phenyl-1H-indole, C22H17ClN2O2, (IV). The dominant inter-molecular inter-action in each case is an N-H⋯O hydrogen bond, which generates either chains or inversion dimers. Weak C-H⋯O, C-H⋯π and π-π inter-actions occur in these structures but there is no consistent pattern amongst them. Two of these compounds act as modest enhancers of CB1 cannabanoid signalling and two are inactive.

Peptide macrocycles are found in many biologically active natural products. Their versatility, resistance to proteolysis and ability to traverse membranes has made them desirable molecules. Although technologies exist to synthesize such compounds, the full extent of diversity found among natural macrocycles has yet to be achieved synthetically. Cyanobactins are ribosomal peptide macrocycles encompassing an extraordinarily diverse range of ring sizes, amino acids and chemical modifications. We report the structure, biochemical characterization and initial engineering of the PatG macrocyclase domain of Prochloron sp. from the patellamide pathway that catalyzes the macrocyclization of linear peptides. The enzyme contains insertions in the subtilisin fold to allow it to recognize a three-residue signature, bind substrate in a preorganized and unusual conformation, shield an acyl-enzyme intermediate from water and catalyze peptide bond formation. The ability to macrocyclize a broad range of nonactivated substrates has wide biotechnology applications.

We describe for the first time the synthesis of biocompatible TiO2 nanoparticles containing a functional NH2 group which are easily dispersible in water. The synthesis of water dispersible TiO2 nanoparticles coated with mercaptosuccinic acid is also reported. We show that it is possible to exchange the stearic acid from pre-synthesised fatty acid-coated anatase 5-nm nanoparticles with a range of organic ligands with no change in the size or morphology. With further organic functionalisation, these nanoparticles could be used for medical imaging or to carry cytotoxic radionuclides for radioimmunotherapy where ultrasmall nanoparticles will be essential for rapid renal clearance.

A rapid repetitive solution-phase synthesis of peptides is described. The procedure involves coupling of amino acids and peptide acids, instead of the usual amino esters and peptide esters, to slight excesses of pentafluorophenyl active esters in a THF/water solvent mixture. Due to their poor solubility, peptide acid intermediates are easily isolated in high purity by acidification under controlled conditions and removal of excess active esters by selective extraction. Contrary to modern repetitive solution-phase peptide synthesis procedures, our approach does not require time-consuming neutralization reactions and reduces significantly the number of operation units that are necessary to obtain peptide intermediates. Efficiency of the method was demonstrated by the rapid synthesis of short hydrophobic and hydrophilic peptides, the antimalarial cycloheptapeptide mahafacyclin B, and a protected form of the hydrophilic pentapeptide GRGDS.

Galanin is a neuropeptide with a wide variety of biological functions. Few nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin and the tripeptidomimetic galnon, a combinatorial library was formulated, synthesized, and screened against the galanin receptor. An active compound, galmic, was identified and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. The present work describes the total synthesis of galmic, the synthesis of its oxazole precursors, the coupling of the building blocks into a linear trimer, and the macrolactamization reaction.

The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (Ki = 34.2 microM) and virtually no affinity for GalR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.

Alkanes adopt extended conformations in solution that minimize steric interactions and maximize surface area. Folding can reduce the amount of hydrophobic surface exposed to solvent, but sterically unfavorable gauche interactions result. However, we found that the alkyl chains of two common surfactants in aqueous solution adopt helical conformations when bound within a synthetic receptor. The receptor recognizes the helical alkane better than the extended conformation, even though 2 to 3 kilocalories per mole of strain is introduced. The proper filling of space and burial of hydrophobic surface drive the molecular recognition between the receptor and the coiled alkane.