A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects.

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH3 group with phenyl (4), methyl (5), or 3'-furanyl [6 (SC13)] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology. In assays limiting MOR reserve, the G-protein efficacy of all three was comparable to buprenorphine. 6 (SC13) showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning in mice. These results suggest the possibility of activating MOR minimally (G-protein Emax ≈ 10%) in cell lines while yet attaining maximal antinociception in vivo with reduced opioid liabilities.

Total Synthesis of (-)-Arborisidine.

An asymmetric total synthesis of cage-like indole alkaloid arborisidine is presented. The new synthetic strategy features a catalytic parallel kinetic resolution based on ambident nucleophilicity (C3/N) of indole to set the absolute configurations of the two quaternary chiral centers, and a 5-exo-trig radical cyclization to form the bridged nitrogen-containing five-membered ring.

Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

Total Syntheses of (-)-Strictosidine and Related Indole Alkaloid Glycosides.

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet-Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (-)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet-Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (-)-strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (-)-strictosamide, (-)-neonaucleoside A, (-)-cymoside, and (-)-3α-dihydrocadambine.

Total Syntheses of Lycopodium and Monoterpenoid Indole Alkaloids Based on Biosynthesis-Inspired Strategies.

The merits of biogenetic considerations in the chemical syntheses of natural products have been emphasized by describing the total syntheses of Lycopodium alkaloids; lycodine, flabellidine, lycopodine, and flabelliformine, as well as monoterpenoid indole alkaloids; C-mavacurine, kopsiyunnanine K, koumine, and 11-methoxy-19R-hydroxygelselegine.

Stereocontrolled Synthesis of (±)-Melokhanine E via an Intramolecular Formal [3 + 2] Cycloaddition.

A convergent sequence to access the indole alkaloid (±)-melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3 + 2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported efforts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.

Stereoselective Total Synthesis of (±)-Alstoscholarisine E.

The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in seven linear steps from commercially available reagents and 15.2% overall yield. The approach features a tandem vinylogous Mannich reaction and hetero-Diels-Alder reaction to access the core. A novel tactic to induce diastereoselective reduction of the cyclic vinyl ether was discovered, and a mild procedure to form the bridged aminal ring by partial reduction of the lactam ring via iridium-catalyzed hydrosilylation was developed.

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization.

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.

Total Synthesis of (+)-Arborisidine.

The first total synthesis of arborisidine, a unique Kopsia indole alkaloid possessing a fully substituted cyclohexanone ring system with two quaternary carbons, has been achieved in seven steps in racemic format from tryptamine and in nine steps in asymmetric format from d-tryptophan methyl ester. Key elements of the design include a carefully orchestrated decyanation protocol to finalize the asymmetric formation of an aza-quaternary center that is challenging to access in optically active format via direct Pictet-Spengler cyclizations with tryptamine, a metal-promoted 6- endo-dig cyclization of an enyne to establish the second core quaternary center, and regiospecific functionalizations of the resultant complex diene to finalize the target structure. The distinct and efficient nature of the developed solution is highlighted by several unsuccessful approaches and unexpected rearrangements.

Synthesis of Alstoscholarisines A-E, Monoterpene Indole Alkaloids with Modulating Effects on Neural Stem Cells.

A divergent synthetic strategy has been developed for stereoselective total syntheses of alstoscholarisines A-E, monoterpenoid indole alkaloids which are modulators of adult neuronal stem cells. A pivotal step includes an intermolecular Michael addition of an indole-2-acetic acid methyl ester enolate to an α,ß-unsaturated N-sulfonyllactam to form the C15, C16 bond of the alkaloids. Other features of the strategy involve a selective partial reduction of an intermediate N-sulfonyllactam followed by cyclization to a bridged aminal system that serves as a key precursor for all five of the alkaloids as well as the use of an allyl group as a masked aldehyde equivalent.

Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies.

The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2( S)-cathafoline, (+)-akuammiline, and (-)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof.

Design and synthesis of novel monoterpenoid indole alkaloid-like analogues and their antitumour activities in vitro.

A biomimetic synthetic strategy and combinatorial chemistry were used to synthesize 34 novel monoterpenoid indole alkaloid (MIA) analogues, and their cytotoxic activities against five cancer cell lines (SW-480, A-549, HL-60, SMMC-7721, and MCF-7) were determined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Fourteen of these analogues (7, 16-18, and 23-32) showed significantly greater inhibition of tumour cell proliferation than cisplatin. Compounds 17 and 18 showed the highest cytotoxic activity against the HL-60 cell line with IC50 values of 0.90 µM and 0.43 µM, respectively. Compound 18 slightly induced apoptosis and arrested the cell cycle in SW-480, A-549, HL-60, SMMC-7721, and MCF-7 cells. Analysis of the primary structure-activity relationships reveals that the introduction of different substituent groups at the C-3, C-5, and C-6 positions of the indole moiety and the C-10 position of the genipin moiety might have an effect on the antitumour activity of the resulting compounds.

Short Synthesis of the Monoterpene Indole Alkaloid (±)-Arbornamine.

The first total synthesis of the monoterpene indole alkaloid (±)-arbornamine (1) has been completed, which proceeds in only 6 steps and 31% overall yield from three readily available, known compounds. The synthesis features a cascade involving a Pictet-Spengler cyclization/intramolecular ammonolysis to create the tetracyclic core of arbornamine (1) in a single chemical operation. The subsequent elaboration of 5 into 1 was effected by a key reductive Heck reaction and global reduction.

Arborisidine and Arbornamine, Two Monoterpenoid Indole Alkaloids with New Polycyclic Carbon-Nitrogen Skeletons Derived from a Common Pericine Precursor.

Two new monoterpene indole alkaloids, characterized by previously unencountered natural product skeletons, viz., arborisidine (1), incorporating indolizidine and cyclohexanone moieties fused to an indole unit, and arbornamine (2), incorporating an unprecedented 6/5/6/5/6 "arbornane" skeleton (distinct from the eburnan or tacaman skeleton), were isolated from a Malayan Kopsia arborea. The structures of the alkaloids were determined based on analysis of the NMR and MS data. Possible biogenetic pathways to these alkaloids from a common pericine precursor (3) are presented.

Synthesis and Cytoxicity of Sempervirine and Analogues.

Sempervirine and analogues were synthesized using a route featuring Sonogashira and Larock Pd-catalyzed reactions. Structure-activity relationships were investigated using three human cancer cell lines. 10-Fluorosempervirine is the most potently cytotoxic member of the family yet described.

Enantioselective Total Synthesis of (-)-Alstoscholarisine A.

We report a concise and highly enantioselective total synthesis of (-)-alstoscholarisine A (1), a recently isolated monoterpenoid indole alkaloid that has significant bioactivity in promoting adult neuronal stem cells proliferation. A highly enantioselective (99% ee), intramolecular Ir-catalyzed Friedel-Crafts alkylation of indole 9 with a secondary allylic alcohol was utilized to establish the first stereogenic center upon which the other three contiguous chiral centers were readily set by a highly stereoselective tandem 1,4-addition and aldol reaction. The key tetrahydropyran was constructed through a hemiacetal reduction, and the final aminal bridge was forged by a one-pot reductive amination/cyclization. The conciseness of this approach was highlighted by building core bonds in each step with a minimalist protecting group strategy.

Alstoscholarisines H-J, Indole Alkaloids from Alstonia scholaris: Structural Evaluation and Bioinspired Synthesis of Alstoscholarisine H.

Alstoscholarisines H-J (1-3), new monoterpenoid indole alkaloids with an unprecedented skeleton created via the formation of a C-3/N-1 bond, were isolated from Alstonia scholaris. Their structures were established by extensive spectroscopic analyses and the assessment of single-crystal X-ray diffraction data. The total synthesis of alstoscholarisine H was achieved via the regioselective nucleophilic addition of pyridinium through a bioinspired iminium ion intermediate followed by Pictet-Spengler-like cyclization.

The use of residual dipolar coupling for conformational analysis of structurally related natural products.

Determining the conformational preferences of molecules in solution remains a considerable challenge. Recently, the use of residual dipolar coupling (RDC) analysis has emerged as a key method to address this. Whilst to date the majority of the applications have focused on biomolecules including proteins and DNA, the use of RDCs for studying small molecules is gaining popularity. Having said that, the method continues to develop, and here, we describe an early case study of the quantification of conformer populations in small molecules using RDC analysis. Having been inspired to study conformational preferences by unexpected differences in the NMR spectra and the reactivity of related natural products, we showed that the use of more established techniques was unsatisfactory in explaining the experimental observations. The use of RDCs provided an improved understanding that, following use of methods to quantify conformer populations using RDCs, culminated in a rationalisation of the contrasting diastereoselectivities observed in a ketone reduction reaction.

A photoinduced cyclization cascade-total synthesis of (-)-leuconoxine.

A protecting-group-free and enantioselective total synthesis of the monoterpenoid indole alkaloid (-)-leuconoxine was accomplished. The key step comprises a novel photoinduced domino macrocyclization/transannular cyclization involving the Witkop cyclization, for which additional mechanistic evidence is provided. This process furnishes a diaza[5.5.6.6]fenestrane skeleton, which is a hitherto unprecedented structure element.

Biosynthetically inspired divergent approach to monoterpene indole alkaloids: total synthesis of mersicarpine, leuconodines B and D, leuconoxine, melodinine E, leuconolam, and rhazinilam.

Inspired by their potential biosynthesis, we have developed divergent total syntheses of seven monoterpene indole alkaloids including mersicarpine, leuconodines B and D, leuconoxine, melodinine E, leuconolam, and rhazinilam, and one unnatural analogue with an unprecedented structural skeleton. The key steps involve a Witkop-Winterfeldt oxidative indole cleavage followed by transannular cyclization. The transannular cyclization product was then converted to the corresponding structural skeletons by pairing its functional groups into different reaction modes.