Aspidosperma and Strychnos alkaloids: Chemistry and biology.

Of Nature's nearly 3000 unique monoterpene indole alkaloids derived from tryptophan, those members belonging to the Aspidosperma and Strychnos families continue to impact the fields of natural products (i.e., isolation, structure determination, biosynthesis) and organic chemistry (i.e., chemical synthesis, methodology development) among others. This review covers the biological activity (Section 2), biosynthesis (Section 3), and synthesis of both classical and novel Aspidosperma (Section 4), Strychnos (Section 5), and selected bis-indole (Section 6) alkaloids. Technological advancements in genetic sequencing and bioinformatics have deepened our understanding of how Nature assembles these intriguing molecules. The proliferation of innovative synthetic strategies and tactics for the synthesis of the alkaloids covered in this review, which include contributions from over fifty research groups from around the world, are a testament to the creative power and technical skills of synthetic organic chemists. To be sure, Nature-the Supreme molecular architect and source of a dazzling array of irresistible chemical logic puzzles-continues to inspire scientists across multiple disciplines and will certainly continue to do so for the foreseeable future.

Synthesis of (-)-Melodinine K: A Case Study of Efficiency in Natural Product Synthesis.

Efficiency is a key organizing principle in modern natural product synthesis. Practical criteria include time, cost, and effort expended to synthesize the target, which tracks with step-count and scale. The execution of a natural product synthesis, that is, the sum and identity of each reaction employed therein, falls along a continuum of chemical (abiotic) synthesis on one extreme, followed by the hybrid chemoenzymatic approach, and ultimately biological (biosynthesis) on the other, acknowledging the first synthesis belongs to Nature. Starting materials also span a continuum of structural complexity approaching the target with constituent elements on one extreme, followed by petroleum-derived and "chiral pool" building blocks, and complex natural products (i.e., semisynthesis) on the other. Herein, we detail our approach toward realizing the first synthesis of (-)-melodinine K, a complex bis-indole alkaloid. The total syntheses of monomers (-)-tabersonine and (-)-16-methoxytabersonine employing our domino Michael/Mannich annulation is described. Isolation of (-)-tabersonine from Voacanga africana and strategic biotransformation with tabersonine 16-hydroxylase for site-specific C-H oxidation enabled a scalable route. The Polonovski-Potier reaction was employed in biomimetic fragment coupling. Subsequent manipulations delivered the target. We conclude with a discussion of efficiency in natural products synthesis and how chemical and biological technologies define the synthetic frontier.

In vivo Antimalarial and Antitrypanosomal Activity of Strychnogucine B, a Bisindole Alkaloid from Strychnos icaja.

Strychnogucine B is a bisindole alkaloid previously isolated from Strychnos icaja that possesses promising in vitro antiplasmodial properties. This compound was synthesized in four steps from (-)-strychnine. As no acute toxicity was observed at the highest tested cumulative dose of 60 mg/kg, its in vivo antimalarial activity was determined intraperitoneally at 30 mg/kg/d in a Plasmodium berghei murine model. In the Peters's 4-d suppressive test, this alkaloid suppressed the parasitaemia by almost 36% on day 5 and 60% on day 7 compared to vehicle-treated mice. In addition to this interesting antimalarial activity, it showed moderate in vitro antitrypanosomal activity but no in vivo activity in an acute Trypanosoma brucei model. It was also inactive in vitro on Leishmania mexicana promastigotes. This highlights its selective antimalarial efficacy and leads to further investigation to assess its potential as new antimalarial lead compound.

Englerins: A Comprehensive Review.

In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.

Development and Scope of the Arene-Fused Domino Michael/Mannich Reaction: Application to the Total Syntheses of Aspidosperma Alkaloids (-)-Aspidospermidine, (-)-Tabersonine, and (-)-Vincadifformine.

The development and application of the arene-fused domino Michael/Mannich route to the tetrahydrocarbazole (ABE) core of Aspidosperma alkaloids is described. The scope of this novel transformation was studied in terms of the nucleophilic component (i.e., N-sulfinyl metallodienamine) and the electrophilic component (i.e., Michael acceptor). The successful application of this methodology toward the concise total syntheses of classical indole alkaloids (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine in 10-11 steps, respectively, is also discussed.

Concise Syntheses of bis-Strychnos Alkaloids (-)-Sungucine, (-)-Isosungucine, and (-)-Strychnogucine†B from (-)-Strychnine.

The first chemical syntheses of complex, bis-Strychnos alkaloids (-)-sungucine (1), (-)-isosungucine (2), and (-)-strychnogucine B (3) from (-)-strychnine (4) is reported. Key steps included (1) the Polonovski-Potier activation of strychnine N-oxide; (2) a biomimetic Mannich coupling to forge the signature C23-C5' bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH3 CN-mediated reduction to fashion the ethylidene moieties in 1-3. DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.

Synthesis and biological evaluation of pentacyclic strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump.

The selective modulation of ATP-binding cassette (ABC) efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represent a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (2), F (3), and A (5) and N-demethylalstogucine (4), in addition to known Strychnos alkaloid echitamidine (16), and we evaluated compounds 1-5 in biochemical assays with ABCC10 and P-glycoprotein (P-gp). Alstolucines B (2) and F (3) inhibited ABCC10 ATPase activity at 12.5 µM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 µM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump.

Domino Michael/Mannich/N-alkylation route to the tetrahydrocarbazole framework of aspidosperma alkaloids: concise total syntheses of (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine.

We report a novel, asymmetric domino Michael/Mannich/N-alkylation sequence for the rapid assembly of the tetrahydrocarbazole framework of Aspidosperma alkaloids. This method was utilized in the concise total syntheses of classical targets (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine in 10 or 11 steps. Additional key steps include ring-closing metathesis to prepare the D-ring and Bosch-Rubiralta spirocyclization to prepare the C-ring.

Architectural spiroligomers designed for binuclear metal complex templating.

The first structurally, spectroscopically, and electronically characterized metal-spiroligomer complexes are reported. The binuclear [M2L2](4+) ions (M = Mn, Zn) are macrocyclic "squares" and are characterized by X-ray diffraction, (1)H and (13)C NMR, electronic absorption, emission, and mass spectroscopies. The manganese complex contains two spin-independent Mn(II) ions and is additionally characterized using EPR and CD spectroscopies and CV.