Family Of Alkaloids Research Articles

A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L−1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.

Total Synthesis Provides Strong Evidence: Xestocyclamine A is the Enantiomer of Ingenamine.

Xestocyclamine A ((−)-1) is featured prominently in a biosynthesis pathway leading to a large family of polycyclic alkaloids. The first total synthesis now proves that the structure of this compound had originally been misassigned. The route to (−)-1 is based on a double Michael addition for the formation of the bridged diazadecalin core and a palladium-catalyzed decarboxylative allylation to install the quaternary bridgehead center. Ring-closing alkyne metathesis allowed a 13-membered cycloalkyne to be forged, which was selectively reduced during an involved sequence of hydroboration/selective protodeborylation/alkyl-Suzuki coupling used to close the 11-membered ring. Crystallographic data prove the identity of synthetic (−)-1 with nominal xestocyclamine, but the spectra differ from those of the authentic alkaloid. To clarify the point, the synthesis was redirected toward ingenamine (3), which is supposedly a positional isomer of 1. The recorded data confirm the assignment of this particular natural product and strongly suggest that xestocyclamine A is in fact the enantiomer of ingenamine (+)-3.

A New Approach to the Total Synthesıs of (±)-Nordasycarpıdone by Rıng-closure wıth Tetrachloro-1,4-benzoquınone

A new synthetic route for the (±)-nordasycarpidone was achieved in five steps with an overall yield of 41%. This route involves ring closure and formation of 5 which has a methanoazocino[4,3-b]indole skeleton in the key step. The reaction also involved a cyclization reaction of tetrahydrocarbazole with a monoalkyl nitrile side chain at the C-2 position, and this reaction was mediated by tetrachloro-1,4-benzoquinone (TCB). The central step in the synthesis was the closure of the D-ring of the intra-molecular structure and the addition of amine, which resulted in an aza-tetracyclic substructure that contained the ABCD-ring of the strychnos alkaloid family.

Total Synthesis of (±)‐Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen‐Oxygen Bonds

AbstractThe development of a concise total synthesis of (±)‐phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen‐oxygen (N−O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early‐stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N−O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.

Total Synthesis of (±)-Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen-Oxygen Bonds.

The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen-oxygen (N-O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early-stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N-O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.

Towards the Sarpagine-Ajmaline-Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N-Demethyl Alstolactone Diastereomer.

the strategy involving the use of functionalized tetrahydro-6H-cycloocta[b]indol-6-one is reported as a key intermediate for synthesis of members of the sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans' syn-selective aldolization; 2) Liebeskind-Srogl cross-coupling using the phenylthiol ester of 3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; and 3) ring-closing metathesis (RCM) for the formation of the eight-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.

3-(2-Isocyanoethyl)indole: A Versatile Reagent for Polycyclic Spiroindoline Synthesis

Polycyclic spiroindolines are the basic skeletons of large families of indole alkaloids that exhibit a broad spectrum of biological and pharmacological activities. The past seven years have seen impressive developments in the construction of polycyclic spiroindolines enabled by 3-(2-isocyanoethyl)indole-based cascade reactions. We herein give a brief summary on this evolution and highlight our contributions in this field.1 Introduction2 Cascade Reactions Involving Nitrilium Ion Intermediates3 Cascade Reactions Involving Ketenimine Intermediates4 Conclusion and Outlook

Vinblastine and vincristine as anticancer molecules stopping the tubulin dimers

Vinblastine is belonging to vinca alkaloid family which is a chemical analogue of vincristine molecules. It has a high potential for attaching to tubulin of microtubules, therefore inhibiting the assembly of that biomolecules. Human EGFRs receptors are cell surfaces receptors proteins including three different domains which are known extracellular ligand-binding domain, trans-membranes hydrophobic domain and cytoplasmic C-terminal domain with tyrosine kinase. The Chemical & physical vibrational spectral data obtained from NMR, NBO and IR spectra based on the results of the theoretical calculations using DFT and HF methods. The fundamental vibrational modes were characterized depending on the stabilities of Herceptin in different dielectric constants. Thus, the goal of this article is to evaluate and quantify and qualify of the mechanism in various solvents.

Construction of key building blocks towards the synthesis of cortistatins.

This work reports the construction of key building blocks towards the synthesis of cortistatins; a family of steroidal alkaloids. Cortistatin A, being a primary target due to its superior biological properties over other congeners, has been prepared by two different synthetic routes. Synthesis of the precursor to the heavily substituted A-ring starting from d-glucose and construction of the DE-ring junction employing a Hajos-Parrish ketone as a chiral pool have been demonstrated. Efforts are underway to assemble these key fragments and build towards the total synthesis of cortistatin A.

Synthetic studies toward longeracemine: a SmI2-mediated spirocyclization and rearrangement cascade to construct the 2-azabicyclo[2.2.1]heptane framework.

Longeracemine, a member of the Daphniphyllum family of alkaloids contains a novel carbon framework featuring a highly functionalized 2-azabicyclo[2.2.1]heptane core as part of an overall 5/6/5/5/6/5 skeleton. A synthetic intermediate containing the core of longeracemine has been efficiently prepared by employing a stereoselective SmI2-mediated cascade reaction to advance a 7-azabicyclo[2.2.1]heptadiene to a 2-azabicyclo[2.2.1]heptene that is functionally poised for conversion to the natural product.

Cytisine exerts anti-tumour effects on lung cancer cells by modulating reactive oxygen species-mediated signalling pathways

Cytisine is a natural product isolated from plants and is a member of the quinolizidine alkaloid family. This study aims to investigate the effect of cytisine in human lung cancer. Cell viability was determined using the CCK-8 assay, and the results showed that cytisine inhibited the growth of lung cancer cell lines. The apoptotic effects were evaluated using flow cytometry, and the results showed that cytisine induced mitochondrial-dependent apoptosis through loss of the mitochondrial membrane potential; increased expression of BAD, cleaved caspase-3, and cleaved-PARP; and decreased expression levels of Bcl-2, pro-caspase-3, and pro-PARP. In addition, cytisine caused G2/M phase cell cycle arrest that was associated with inhibiting the AKT signalling pathway. During apoptosis, cytisine increased the phosphorylation levels of JNK, p38, and I-κB, and decreased the phosphorylation levels of ERK, STAT3, and NF-κB. Furthermore, cytisine treatment led to the generation of ROS, and the NAC attenuated cytisine-induced apoptosis. In vivo, cytisine administration significantly inhibited the lung cancer cell xenograft tumorigenesis. In conclusion, cytisine plays a critical role in suppressing the carcinogenesis of lung cancer cells through cell cycle arrest and induction of mitochondria-mediated apoptosis, suggesting that it may be a promising candidate for the treatment of human lung cancer.

Total Synthesis of Talatisamine

AbstractTalatisamine (1) is a member of the C19‐diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5‐membered‐ring structure (ABCDEF‐ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6‐membered AE‐ring 7 and aromatic 6‐membered D‐ring 6. AE‐ring 7 was constructed from 2‐cyclohexenone (8) through fusing an N‐ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels–Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6‐membered ring system was then stereospecifically reorganized into the 7/5‐membered BC‐ring of 3 via a Wagner–Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza‐Prins cyclization of 2, thereby forging the remaining 5‐membered F‐ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8.

Total Synthesis of Talatisamine.

Talatisamine (1) is a member of the C19 -diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5-membered-ring structure (ABCDEF-ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6-membered AE-ring 7 and aromatic 6-membered D-ring 6. AE-ring 7 was constructed from 2-cyclohexenone (8) through fusing an N-ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels-Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6-membered ring system was then stereospecifically reorganized into the 7/5-membered BC-ring of 3 via a Wagner-Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza-Prins cyclization of 2, thereby forging the remaining 5-membered F-ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8.

Antiamoebic Activities of Indolocarbazole Metabolites Isolated from Streptomyces sanyensis Cultures.

Indolocarbazoles are a family of natural alkaloids characterized by their potent protein kinase and topoisomerase I inhibitory activity. Among them, staurosporine (1) has exhibited promising inhibitory activity against parasites. Based on new insights on the activity and mechanism of action of STS in Acanthamoeba parasites, this work reports the isolation, identification, and the anti-Acanthamoeba activity of the minor metabolites 7-oxostaurosporine (2), 4′-demethylamino-4′-oxostaurosporine (3), and streptocarbazole B (4), isolated from cultures of the mangrove strain Streptomyces sanyensis. A clear correlation between the antiparasitic activities and the structural elements and conformations of the indolocarbazoles 1–4 was observed. Also, the study reveals that 7-oxostaurosporine (2) affects membrane permeability and causes mitochondrial damages on trophozoites of A. castellanii Neff.

NMR characterization of rearranged staurosporine aglycone analogues from the marine sponge Damiria sp.

The indolocarbazole family of bisindole alkaloids is best known for the natural product staurosporine, a protein kinase C inhibitor that belongs to the indolo[2,3-a]carbazole structural class. A large number of other indolo[2,3-a]carbazoles have subsequently been isolated and identified, but other isomeric forms of indolocarbazole natural products have rarely been reported. An extract of the marine sponge Damiria sp., which represents an understudied genus, provided two novel alkaloids named damirines A (1) and B (2). Their structures were assigned by comprehensive NMR spectroscopic analyses, and for compound 2, this included application of the LR-HSQMBC pulse sequence, a long-range heteronuclear correlation experiment that has particular utility for defining proton-deficient scaffolds. The damirines represent a new hexacyclic carbon-nitrogen framework comprised of an indolo[3,2-a]carbazole fused with either an aminoimidazole or a imidazolone ring. Compound 1 showed selective cytotoxic properties toward six different cell lines in the NCI-60 cancer screen.

Engineered Production of Hapalindole Alkaloids in the Cyanobacterium Synechococcus sp. UTEX 2973.

Cyanobacteria produce numerous valuable bioactive secondary metabolites (natural products) including alkaloids, isoprenoids, nonribosomal peptides, and polyketides. However, the genomic organization of the biosynthetic gene clusters, complex gene expression patterns, and low compound yields synthesized by the native producers currently limits access to the vast majority of these valuable molecules for detailed studies. Molecular cloning and expression of such clusters in heterotrophic hosts is often precarious owing to genetic and biochemical incompatibilities. Production of such biomolecules in photoautotrophic hosts analogous to the native producers is an attractive alternative that has been under-explored. Here, we describe engineering of the fast-growing cyanobacterium Synechococcus elongatus UTEX 2973 to produce key compounds of the hapalindole family of indole-isonitrile alkaloids. Engineering of the 42-kbp "fam" hapalindole pathway from the cyanobacterium Fischerella ambigua UTEX 1903 into S2973 was accomplished by rationally reconstructing six to seven core biosynthetic genes into synthetic operons. The resulting Synechococcus strains afforded controllable production of indole-isonitrile biosynthetic intermediates and hapalindoles H and 12-epi-hapalindole U at a titer of 0.75-3 mg/L. Exchanging genes encoding fam cyclase enzymes in the synthetic operons was employed to control the stereochemistry of the resulting product. Establishing a robust expression system provides a facile route to scalable levels of similar natural and new forms of bioactive hapalindole derivatives and its structural relatives (e.g., fischerindoles, welwitindolinones). Moreover, this versatile expression system represents a promising tool for exploring other functional characteristics of orphan gene products that mediate the remarkable biosynthesis of this important family of natural products.

The Hancock Alkaloids Angustureine, Cuspareine, Galipinine, and Galipeine: A Review of their Isolation, Synthesis, and Spectroscopic Data

A review of the isolation, reported methods for the synthesis (up to the end of 2018), and spectroscopic data of angustureine, cuspareine, galipinine, and galipeine, members of the Hancock family of alkaloids based upon a 2‐substituted N(1)‐methyl‐1,2–3,4‐tetrahydroisolquinoline scaffold, is presented.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids.

Reported is the enantioselective total syntheses of mavacuran alkaloids, (+)-taberdivarine H, (+)-16-hydroxymethyl-pleiocarpamine, and (+)-16-epi-pleiocarpamine, and their postulated biosynthetic precursor 16-formyl-pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1-C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids

AbstractReported is the enantioselective total syntheses of mavacuran alkaloids, (+)‐taberdivarine H, (+)‐16‐hydroxymethyl‐pleiocarpamine, and (+)‐16‐epi‐pleiocarpamine, and their postulated biosynthetic precursor 16‐formyl‐pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1−C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.

Phytochemistry and neuroprotective effects of Eclipta alba (L.) Hassk.

Eclipta alba (L.) Hassk. or Eclipta prostrata (Linn.) or Eclipta erecta (Linn.) is an herbaceous plant well known in Asian as African traditional medicines. These extracts are used in traditional medicine for treatment of microbial diseases and certain metabolic disorders. This review aimed to investigate phytochemical profile and neuroprotective effects of E. alba (L.) Hassk. Several compounds belonging to the families of phenolics, alkaloids, terpenoids and polysaccharides have been isolated, identified or characterized from E. alba extracts. This plant has a diverse neuropharmacological profile. Thus, its extract improves cognitive deficits and also attenuated epileptic seizures. Phytomolecules implicated in these potentials are Eclalbasaponin II and luteolin, respectively. This document updates isolated and identified organic compounds from the extracts of E. alba and reviews their neuropharmacological activities.