Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 97
Filter
Add more filters










Publication year range
1.
Chembiochem ; 23(3): e202100517, 2022 02 04.
Article in English | MEDLINE | ID: mdl-34767291

ABSTRACT

Indolizidine alkaloids, which have versatile bioactivities, are produced by various organisms. Although the biosynthesis of some indolizidine alkaloids has been studied, the enzymatic machinery for their biosynthesis in Streptomyces remains elusive. Here, we report the identification and analysis of the biosynthetic gene cluster for iminimycin, an indolizidine alkaloid with a 6-5-3 tricyclic system containing an iminium cation from Streptomyces griseus. The gene cluster has 22 genes, including four genes encoding polyketide synthases (PKSs), which consist of eight modules in total. In vitro analysis of the first module revealed that its acyltransferase domain selects malonyl-CoA, although predicted to select methylmalonyl-CoA. Inactivation of seven tailoring enzyme-encoding genes and structural elucidation of four compounds accumulated in mutants provided important insights into iminimycin biosynthesis, although some of these compounds appeared to be shunt products. This study expands our knowledge of the biosynthetic machinery of indolizidine alkaloids and the enzymatic chemistry of PKS.


Subject(s)
Alkaloids/biosynthesis , Multigene Family , Streptomyces griseus/chemistry , Streptomyces griseus/genetics , Alkaloids/chemistry , Indolizidines/chemistry , Molecular Conformation , Streptomyces griseus/metabolism
2.
Int J Mol Sci ; 22(15)2021 Jul 25.
Article in English | MEDLINE | ID: mdl-34360698

ABSTRACT

Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6ß2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6ß2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6ß2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6ß2 nAChR that we derived from the recent crystal structure of α4ß2 nAChR. We also screened the crystal structure of α4ß2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6ß2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.


Subject(s)
Drug Discovery , Indolizidines/chemistry , Molecular Dynamics Simulation , Receptors, Nicotinic/chemistry , Humans , Nicotinic Antagonists/chemistry , Protein Binding , Receptors, Nicotinic/metabolism , Smoking Cessation
3.
J Am Chem Soc ; 143(7): 2970-2983, 2021 02 24.
Article in English | MEDLINE | ID: mdl-33570388

ABSTRACT

Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C10N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C10N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.


Subject(s)
Alkaloids/chemical synthesis , Indole Alkaloids/chemical synthesis , Alkaloids/chemistry , Azepines/chemistry , Bipolaris/chemistry , Bipolaris/metabolism , Crystallography, X-Ray , Curvularia/chemistry , Curvularia/metabolism , Cyclization , Indole Alkaloids/chemistry , Indolizidines/chemistry , Molecular Conformation , Pyrroles/chemistry , Stereoisomerism
4.
J Am Chem Soc ; 142(30): 13041-13050, 2020 07 29.
Article in English | MEDLINE | ID: mdl-32627545

ABSTRACT

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-ß-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-ß-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.


Subject(s)
Aza Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Indolizidines/chemical synthesis , Cyclization , Heterocyclic Compounds/chemistry , Indolizidines/chemistry , Molecular Structure , Stereoisomerism
5.
Sci Rep ; 10(1): 9564, 2020 06 12.
Article in English | MEDLINE | ID: mdl-32533030

ABSTRACT

Two new indolizidine alkaloids crepidatumines A (1) and B (2) together with the stereoisomer of dendrocrepidine B (3) and known analog dendrocrepine (4) were isolated from D. crepidatum. Their structures were determined by HR-ESI-MS, NMR, and Electronic Circular Dichroism (ECD) experiments together with comparison of analogues. Compound (1) possess a (5/6/6/5) tetra-hetero-cyclic ring, whereas compound (2) contains a tricyclic system with an unusual bridged ring, which are the first report in Nature. The biological evaluation revealed that dendrocrepine (4) displayed a potent hypoglycemic effect in vitro.


Subject(s)
Alkaloids/chemistry , Dendrobium/chemistry , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Indolizidines/chemistry , Animals , Cell Proliferation , Glucose/metabolism , Hep G2 Cells , Humans , Mice , RAW 264.7 Cells
6.
Molecules ; 24(17)2019 Aug 23.
Article in English | MEDLINE | ID: mdl-31450800

ABSTRACT

Two new indolizidine alkaloids, crepidatumines C (1) and D (2), together with crepidine (3), isocrepidamine (4), and crepidamine (5) were isolated from the Dendrobium crepidatum Lindl. ex Paxt. X-ray diffraction experiments established the absolute configurations of known compounds 3 and 4. The planar structures and relative configurations of new compounds 1 and 2 were elucidated by extensive spectra analysis including HR-ESI-MS, NMR (1H, 13C, 1H-1H COSY, HSQC, HMBC, and NOESY spectra), and the absolute configurations of 1 and 2 were suggested on the basis of possible biosynthetic pathways. The biological results confirmed that isocrepidamine (4) displayed a potent hypoglycemic effect in vitro without cytotoxicity.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Dendrobium/chemistry , Indolizidines/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , X-Ray Diffraction
7.
J Med Chem ; 62(9): 4500-4525, 2019 05 09.
Article in English | MEDLINE | ID: mdl-30932486

ABSTRACT

Peptide mimicry employing a combination of aza-amino acyl proline and indolizidinone residues has been used to develop allosteric modulators of the prostaglandin F2α receptor. The systematic study of the N-terminal phenylacetyl moiety and the conformation and side chain functions of the central turn dipeptide residue has demonstrated the sensitive relationships between modulator activity and topology. Examination of aza-Gly-Pro and aza-Phe-Pro analogs 2a and 2b in a murine preterm labor model featuring treatment with lipopolysaccharide demonstrated their capacity to extend significantly (>20 h) the average time of delivery offering new prototypes for delaying premature birth.


Subject(s)
Aza Compounds/therapeutic use , Indolizidines/chemistry , Peptides/therapeutic use , Premature Birth/prevention & control , Proline/analogs & derivatives , Receptors, Prostaglandin/metabolism , Tocolytic Agents/therapeutic use , Allosteric Regulation , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Escherichia coli/chemistry , Female , Lipopolysaccharides , Mice , Molecular Mimicry , Peptides/chemical synthesis , Peptides/chemistry , Pregnancy , Premature Birth/chemically induced , Stereoisomerism , Structure-Activity Relationship , Tocolytic Agents/chemical synthesis , Tocolytic Agents/chemistry , Uterine Contraction/drug effects , Uterus/drug effects
8.
Molecules ; 23(7)2018 Jul 10.
Article in English | MEDLINE | ID: mdl-29996473

ABSTRACT

In this study, 2,3-dihydro-1H-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from Prosopis glandulosa, was evaluated against C. neoformans in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live C. neoformans. Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day (bid) orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live C. neoformans were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against C. neoformans at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered bid (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu.


Subject(s)
Cryptococcosis/drug therapy , Cryptococcosis/microbiology , Cryptococcus neoformans/physiology , Indolizidines/therapeutic use , Prosopis/chemistry , Administration, Oral , Alkaloids/administration & dosage , Alkaloids/chemistry , Alkaloids/pharmacology , Alkaloids/therapeutic use , Animals , BH3 Interacting Domain Death Agonist Protein/metabolism , Body Weight/drug effects , Cryptococcosis/blood , Cryptococcus neoformans/drug effects , Disease Models, Animal , Female , Hep G2 Cells , Humans , Indolizidines/administration & dosage , Indolizidines/blood , Indolizidines/chemistry , Mice , Treatment Outcome
9.
J Nat Prod ; 81(2): 394-399, 2018 02 23.
Article in English | MEDLINE | ID: mdl-29389122

ABSTRACT

Eight new cyclizidine-type alkaloids (1-8) and one known alkaloid (9) were identified from the chemical investigations of a marine-derived actinomycete, Streptomyces sp. HNA39. Among these alkaloids, compounds 3, 7, and 8 contain a chlorine atom, and the known alkaloid, (+)-ent-cyclizidine (9), is now first reported as a natural product. Their structures were elucidated by extensive NMR-spectroscopic analysis and HRESIMS data. The absolute configurations of all of the compounds were established by ECD calculations. Cytotoxicity evaluations of all of the compounds showed that compound 2 exhibited significant activity against the PC3 and HCT116 human-cancer-cell lines with IC50 values of 0.52 ± 0.03 and 8.3 ± 0.1 µM, respectively. Interestingly, compounds 2, 5, 7, and 8 exhibited moderate inhibition against the ROCK2 protein kinase with IC50 values from 7.0 ± 0.8 to 42 ± 3 µM.


Subject(s)
Alkaloids/chemistry , Indolizidines/chemistry , Streptomyces/chemistry , Alkaloids/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Cell Line, Tumor , Chlorine/chemistry , Chlorine/pharmacology , Cytotoxins/chemistry , Cytotoxins/pharmacology , HCT116 Cells , Humans , Indolizidines/pharmacology , Magnetic Resonance Spectroscopy/methods , PC-3 Cells , rho-Associated Kinases/antagonists & inhibitors
10.
Org Biomol Chem ; 15(14): 2953-2961, 2017 Apr 05.
Article in English | MEDLINE | ID: mdl-28291271

ABSTRACT

A homo-chiral synthesis of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine 8 and (7S, 8aS)-octahydro-5,5-dimethylindolizin-7-ol 9, amine building blocks which have found applications within the pharmaceutical industry, is presented. The approach uses a Novozym 435-mediated kinetic resolution of racemic octahydroindolizine (indolizidine) alcohol 13 as a key step (up to 100 g scale).


Subject(s)
Alcohols/chemistry , Indolizidines/chemistry , Indolizidines/chemical synthesis , Lipase/metabolism , Biocatalysis , Chemistry Techniques, Synthetic , Enzymes, Immobilized , Fungal Proteins , Kinetics , Models, Molecular , Molecular Conformation , Stereoisomerism
11.
Chemistry ; 23(3): 533-536, 2017 01 12.
Article in English | MEDLINE | ID: mdl-27805289

ABSTRACT

A facile and convergent approach has been developed for the stereoselective construction of biologically important polyhydroxylated 2-acyl indolizidine framework using aza-Cope rearrangement-Mannich cyclization as a key step. The generality of this methodology is demonstrated with various lactol-tosylates derived from carbohydrates. The presented method provides an easy access to indolizidine- and tetrahydroindolizine-based iminosugar derivatives in good yields.


Subject(s)
Indolizidines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aza Compounds/chemistry , Carbohydrates/chemistry , Crystallography, X-Ray , Cyclization , Indolizidines/chemical synthesis , Molecular Conformation , Stereoisomerism
12.
Mini Rev Med Chem ; 17(12): 1002-1012, 2017.
Article in English | MEDLINE | ID: mdl-27151143

ABSTRACT

BACKGROUND: Plants produce a vast variety of specialized metabolites which can be a rich source for lead compounds for the development of new drugs. Alkaloids are one the largest groups of plant specialized metabolites important for natural product based pharmaceuticals. Of these, lysine (Lys)-derived alkaloids exhibit a wide range of pharmacological properties which are beneficial for humans. For instance they have anticancer, anti-Alzheimer's disease, anti-inflammatory, hypocholesterolemic and antiarrhtymic effects. Lys-derived alkaloids are widely distributed throughout the plant kingdom: they can be found in various species from clubmosses to flowering plants. Lys is one of the most essential amino acids for humans and livestock and is synthesized in the plastids of land plants. Lys-derived alkaloids can be divided into four major groups including quinolizidine, lycopodium, piperidine, and indolizidine alkaloids. Despite the importance of these compounds, the biosynthetic pathways of Lys-derived alkaloids are not well understood. With the exception of indolizidine alkaloids, Lys decarboxylase (LDC) is the enzyme involved in the first committed step of the biosynthesis by catalyzing the transformation of L-Lys into cadaverine. Cadaverine is then oxidized by copper amine oxidase (CuAO) and spontaneously cyclized to Δ1-piperideine Schiff base which is a universal intermediate for the production of various Lys-derived alkaloids. CONCLUSION: In this review, we briefly summarize the recent understanding about the structures, occurrences, analytical procedures, biosyntheses, and potential health effects and medical applications of Lys-derived alkaloids with emphasis on quinolizidine alkaloids (QAs).


Subject(s)
Alkaloids/biosynthesis , Lysine/chemistry , Quinolizidines/chemistry , Alkaloids/chemistry , Indolizidines/chemistry , Lycopodium/chemistry , Lycopodium/metabolism , Piperidines/chemistry , Plants/chemistry , Plants/metabolism
13.
ACS Chem Biol ; 11(12): 3278-3283, 2016 12 16.
Article in English | MEDLINE | ID: mdl-27791349

ABSTRACT

Piperidine and indolizidine are two basic units of alkaloids that are frequently observed in natural and synthetic compounds. Their biosynthesis in natural products is highly conserved and mostly derived from the incorporation of lysine cyclization products. Through in vitro reconstitution, we herein identified a novel pathway involving a group of polyketide-derived indolizidines, which comprises the processes of tandem two-electron thioester reduction, transamination, and imine reduction to convert acyl carrier protein (ACP)-tethered polyketide chains into the piperidine moieties of their indolizidine scaffolds. The enzymes that catalyze the imine reduction are distinct from previous known imine reductases, which have a fold of acyl-CoA dehydrogenase but do not require flavin for reduction. Our results not only provide a new way for the biosynthesis of the basic units of alkaloids but also show a novel class of imine reductases that may benefit the fields of biocatalysis and biomanufacturing.


Subject(s)
Indolizidines/metabolism , Piperidines/metabolism , Polyketides/metabolism , Streptomyces/enzymology , Acyl Carrier Protein/metabolism , Acyl-CoA Dehydrogenases/metabolism , Biosynthetic Pathways , Imines/chemistry , Imines/metabolism , Indolizidines/chemistry , Piperidines/chemistry , Polyketides/chemistry , Streptomyces/metabolism
14.
Chemistry ; 22(34): 11949-53, 2016 Aug 16.
Article in English | MEDLINE | ID: mdl-27418326

ABSTRACT

Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen-containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N-tethered olefins using SmI2 /H2 O. This new umpolung protocol leads to the rapid synthesis of nitrogen-containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond-forming reactions by umpolung radical processes. The reaction advances the SmI2 cyclization platform to the challenging unactivated N-tethered acyl-type radical precursors to access nitrogen-containing architectures.


Subject(s)
Alkaloids/chemical synthesis , Alkenes/chemistry , Amides/chemistry , Indolizidines/chemical synthesis , Iodides/chemistry , Lactams/chemical synthesis , Nitrogen/chemistry , Samarium/chemistry , Water/chemistry , Alkaloids/chemistry , Cyclization , Electron Transport , Esters , Indolizidines/chemistry , Lactams/chemistry , Molecular Structure
15.
Org Biomol Chem ; 14(29): 7084-91, 2016 Aug 07.
Article in English | MEDLINE | ID: mdl-27377480

ABSTRACT

3,5-Dialkyl indolizidines have been prepared in four linear steps from commercially available starting materials. The sequence involves two direct α-functionalization steps and a subsequent reductive amination and provides diastereoselective access to both C-3 epimers of the 5,9-trans-substituted indolizines. The naturally occurring indolizidines 195B and 223AB have been synthesized using this methodology.


Subject(s)
Alkaloids/chemical synthesis , Indolizidines/chemical synthesis , Alkaloids/chemistry , Indolizidines/chemistry , Molecular Structure
16.
Angew Chem Int Ed Engl ; 55(14): 4605-9, 2016 Mar 24.
Article in English | MEDLINE | ID: mdl-26934056

ABSTRACT

A highly adaptable method targeting the ubiquitous and very important pyrrolizidine and indolizidine scaffolds is presented. The general synthetic utility of the method is underscored by its application to the rapid and easy synthesis of five natural products starting from readily accessible alkylfuran precursors. These unprotected primary furylalkylamines are subjected to photooxygenation conditions, which initiate a complex cascade reaction sequence concluding with the production of high value motifs. This sequence can be tailored to need by varying the choice of both photosensitizer and base additive.


Subject(s)
Amines/chemistry , Indolizidines/chemistry , Oxygen/chemistry , Photochemical Processes , Pyrrolizidine Alkaloids/chemistry
17.
Alkaloids Chem Biol ; 75: 1-498, 2016.
Article in English | MEDLINE | ID: mdl-26777309

ABSTRACT

This review of simple indolizidine and quinolizidine alkaloids (i.e., those in which the parent bicyclic systems are in general not embedded in polycyclic arrays) is an update of the previous coverage in Volume 55 of this series (2001). The present survey covers the literature from mid-1999 to the end of 2013; and in addition to aspects of the isolation, characterization, and biological activity of the alkaloids, much emphasis is placed on their total synthesis. A brief introduction to the topic is followed by an overview of relevant alkaloids from fungal and microbial sources, among them slaframine, cyclizidine, Steptomyces metabolites, and the pantocins. The important iminosugar alkaloids lentiginosine, steviamine, swainsonine, castanospermine, and related hydroxyindolizidines are dealt with in the subsequent section. The fourth and fifth sections cover metabolites from terrestrial plants. Pertinent plant alkaloids bearing alkyl, functionalized alkyl or alkenyl substituents include dendroprimine, anibamine, simple alkaloids belonging to the genera Prosopis, Elaeocarpus, Lycopodium, and Poranthera, and bicyclic alkaloids of the lupin family. Plant alkaloids bearing aryl or heteroaryl substituents include ipalbidine and analogs, secophenanthroindolizidine and secophenanthroquinolizidine alkaloids (among them septicine, julandine, and analogs), ficuseptine, lasubines, and other simple quinolizidines of the Lythraceae, the simple furyl-substituted Nuphar alkaloids, and a mixed quinolizidine-quinazoline alkaloid. The penultimate section of the review deals with the sizable group of simple indolizidine and quinolizidine alkaloids isolated from, or detected in, ants, mites, and terrestrial amphibians, and includes an overview of the "dietary hypothesis" for the origin of the amphibian metabolites. The final section surveys relevant alkaloids from marine sources, and includes clathryimines and analogs, stellettamides, the clavepictines and pictamine, and bis(quinolizidine) alkaloids.


Subject(s)
Alkaloids/chemistry , Indolizidines/chemistry , Quinolizidines/chemistry , Animals , Marine Biology , Plants/chemistry
18.
J Antibiot (Tokyo) ; 69(8): 611-5, 2016 08.
Article in English | MEDLINE | ID: mdl-26758492

ABSTRACT

A new natural product, designated iminimycin A, was isolated from the cultured broth of a streptomycin-producing microbial strain, Streptomyces griseus OS-3601, via a physicochemical screening method using HP-20, silica gel and ODS column chromatographies and subsequent preparative HPLC. Iminimycin A is an indolizidine alkaloid, containing of an unusual iminium group and a cyclopropane ring with a triene side chain. The absolute configuration of iminimycin A was elucidated by NMR studies and electronic circular dichroism analysis. Iminimycin A shows anti-bacterial activity against Bacillus subtilis, Kocuria rhizophila and Xanthomonas campestris pv. orizae, and cytotoxic activity against HeLa S3 and Jurkat cells with IC50 values of 43 and 36 µM, respectively.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Streptomyces griseus/metabolism , Alkaloids/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Bacillus subtilis/drug effects , Chromatography, High Pressure Liquid/methods , Circular Dichroism , HeLa Cells , Humans , Indolizidines/chemistry , Indolizidines/isolation & purification , Indolizidines/pharmacology , Inhibitory Concentration 50 , Jurkat Cells , Magnetic Resonance Spectroscopy , Micrococcaceae/drug effects , Xanthomonas campestris/drug effects
19.
J Nat Prod ; 79(1): 252-6, 2016 Jan 22.
Article in English | MEDLINE | ID: mdl-26710212

ABSTRACT

A pair of racemic indolizidine enantiomers, (±)-homocrepidine A (1), and a piperidine derivative, homocrepidine B (2), were isolated from Dendrobium crepidatum along with the known alkaloid crepidine (3). The racemic mixture of 1 was separated into a pair of enantiomers, (+)-1 and (-)-1, by HPLC using a chiral chromatographic substrate, which represents the first successful example of resolving indolizidine racemic mixtures. The absolute configurations of (+)-1 and (-)-1 were assigned from single-crystal X-ray diffraction data. The evaluation of anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that (+)-1 strongly inhibited the production of nitric oxide (IC50, 3.6 µM) and significantly decreased the expression of inducible nitric oxide synthase, while (-)-1 and (±)-1 only had moderate inhibitory effects (IC50, 22.8 and 14.7 µM). Compound 2 showed moderate anti-inflammatory activity (IC50, 27.6 µM).


Subject(s)
Alkaloids/isolation & purification , Alkaloids/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Dendrobium/chemistry , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Indolizidines/isolation & purification , Indolizidines/pharmacology , Alkaloids/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Crystallography, X-Ray , Drugs, Chinese Herbal/isolation & purification , Indolizidines/chemistry , Inhibitory Concentration 50 , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Mice , Molecular Conformation , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Piperidines , Plant Stems/chemistry , Stereoisomerism
20.
Chem Biol Drug Des ; 87(2): 200-12, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26212217

ABSTRACT

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti-HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti-HIV activity and the molecules having sulfonamide linkages were the most potent HIV-RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood-brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti-HIV drugs. In vitro screening was performed using HIV-1 strain IIIB in MT-4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV-1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations.


Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Indolizidines/chemistry , Molecular Docking Simulation , Reverse Transcriptase Inhibitors/chemical synthesis , Binding Sites , Blood-Brain Barrier/metabolism , Cell Line , HIV Reverse Transcriptase/metabolism , Humans , Indolizidines/chemical synthesis , Indolizidines/metabolism , Protein Structure, Tertiary , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Thermodynamics
SELECTION OF CITATIONS
SEARCH DETAIL
...