Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold.

A series of amide (8­32, 40­45) and urea (33, 34, 36­39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 µM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.

LAT Transport Inhibitors from Pittosporum venulosum Identified by NMR Fingerprint Analysis.

(1)H NMR fingerprints were used as the guiding principle for the isolation of minor compounds related to the l-type amino acid transporter inhibitors venulosides A (1) and B (2). Two new monoterpene glycosides, namely, venulosides C (3) and D (4), were isolated from a Queensland collection of the plant Pittosporum venulosum. Compounds 3 and 4 were found to inhibit l-leucine transport in LNCaP cells with IC50 values of 11.47 and 39.73 µM, respectively. The venulosides are the first reported natural product inhibitors of leucine transport in prostate cancer cells, and the isolation of the minor compounds provides some early SAR information.

Total synthesis of clavatadine A.

The first total synthesis of the potent and selective human blood coagulation factor XIa inhibitor clavatadine A (1) is described. Direct, early-stage guanidinylation enabled rapid, convergent access to an immediate clavatadine A precursor. Concomitant lactone hydrolysis and guanidine deprotection with aqueous acid cleanly provided clavatadine A (1) in only four steps (longest linear sequence, 41-43% overall yield).

Natural products with anti-Bredt and bridgehead double bonds.

Well over a hundred years ago, Professor Julius Bredt embarked on a career pursuing and critiquing bridged bicyclic systems that contained ring strain induced by the presence of a bridgehead olefin. These endeavors founded what we now know as Bredt's rule (Bredtsche Regel). Physical, theoretical, and synthetic organic chemists have intensely studied this premise, pushing the boundaries of such systems to arrive at a better understood physical phenomenon. Mother nature has also seen fit to construct molecules containing bridgehead double bonds that encompass Bredt's rule. For the first time, this topic is reviewed in a natural product context.

NMR fingerprints of the drug-like natural-product space identify iotrochotazine A: a chemical probe to study Parkinson's disease.

The NMR spectrum of a mixture of small molecules is a fingerprint of all of its components. Herein, we present an NMR fingerprint method that takes advantage of the fact that fractions contain simplified NMR profiles, with minimal signal overlap, to allow the identification of unique spectral patterns. The approach is exemplified in the identification of a novel natural product, iotrochotazine A (1), sourced from an Australian marine sponge Iotrochota sp. Compound 1 was used as a chemical probe in a phenotypic assay panel based on human olfactory neurosphere-derived cells (hONS) from idiopathic Parkinson's disease patients. Compound 1 at 1 µM was not cytotoxic but specifically affected the morphology and cellular distribution of lysosomes and early endosomes.

Recent advances in the total synthesis of cyclopropane-containing natural products.

In this tutorial review, recent advances in the synthesis of cyclopropane-containing natural products are discussed, highlighting the application of novel synthetic methodologies and innovative synthetic strategies in the construction of highly functionalized cyclopropanes. The examples showcased herein aim to inspire students and practitioners of organic synthesis to seek further advances in the chemical synthesis of cyclopropanes, both in the context of target-oriented syntheses and method developments.

The chemistry of the polycyclic polyprenylated acylphloroglucinols.

With their fascinating biological profiles and stunningly complex molecular architectures, the polycyclic polyprenylated acylphloroglucinols (PPAPs) have long provided a fertile playing field for synthetic organic chemists. In particular, the recent advent of innovative synthetic methods and strategies together with C-C bond-forming reactions and asymmetric catalysis have revitalized this field tremendously. Consequently, PPAP targets which once seemed beyond reach have now been synthesized. This Review aims to highlight the recent achievements in the total synthesis of PPAPs, as well as notable methods developed for the construction of the bicyclo[3.3.1] core of these chemically and biologically intriguing molecules.

The clerodane ring system: investigating the viability of a direct Diels-Alder approach.

A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels-Alder approach.

Clarification of the stereochemical course of nucleophilic substitution of arylsulfonate-based nucleophile assisting leaving groups.

Secondary alcohols modified as tosylates, PEG-sulfonates, or quisylates undergo inversion of configuration at the reacting center when treated with lithium halide in acetone at reflux, where the PEG-sulfonates and quisylates are substantially more reactive. In sterically hindered cases, elimination is a competing process. In contrast, when treated with TiCl(4), simple secondary sulfonates give chloride products with partial inversion of configuration. Any observed retention of configuration in a given alkyl sulfonate substrate under these conditions is likely due to neighboring group participation or diastereoselective attack on a carbocation (or ion pair) rather than an S(N)i mechanism.

Bromonium ion induced transannular oxonium ion formation-fragmentation in model obtusallene systems and structural reassignment of obtusallenes V-VII.

Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.

Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space.

A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines.

"One-step" alkynylation of adamantyl iodide with silver(I) acetylides.

[reaction: see text] Silver(I) acetylides allow one-step alkynylation of adamantyl iodide in yields ranging from 25 to 68%.

The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer.

Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.

Monoterpene glycoside ESK246 from Pittosporum targets LAT3 amino acid transport and prostate cancer cell growth.

The L-type amino acid transporter (LAT) family consists of four members (LAT1-4) that mediate uptake of neutral amino acids including leucine. Leucine is not only important as a building block for proteins, but plays a critical role in mTORC1 signaling leading to protein translation. As such, LAT family members are commonly upregulated in cancer in order to fuel increased protein translation and cell growth. To identify potential LAT-specific inhibitors, we established a function-based high-throughput screen using a prefractionated natural product library. We identified and purified two novel monoterpene glycosides, ESK242 and ESK246, sourced from a Queensland collection of the plant Pittosporum venulosum. Using Xenopus laevis oocytes expressing individual LAT family members, we demonstrated that ESK246 preferentially inhibits leucine transport via LAT3, while ESK242 inhibits both LAT1 and LAT3. We further show in LNCaP prostate cancer cells that ESK246 is a potent (IC50 = 8.12 µM) inhibitor of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Our study suggests that ESK246 is a LAT3 inhibitor that can be used to study LAT3 function and upon which new antiprostate cancer therapies may be based.

Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are "Rule-of-5" compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.

Chemical synthesis of the englerins.

In the long lasting battle against cancer, Nature sometimes gives a helping hand to researchers to find new drugs for the treatment of diseases and improvement of patients' well-being. Englerin A has emerged as a promising anticancer candidate as well as being an exciting synthetic challenge for organic chemists. This focus review summarizes the total syntheses reported to date and the synthetic approaches toward analogues of this fascinating natural product.

Two-step regio- and stereoselective synthesis of cis-vinylstannanes.

Herein we describe a novel stereoselective synthesis of cis-vinylstannanes employing the widely established Li/Te exchange pathway. In contrast to previously reported methods of cis-selective hydrostannation (i.e., ZrCl4), this method demonstrates compatibility toward oxygenated substrates.