Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.

Natural glycosaminoglycans (GAGs) are arguably the most diverse collection of natural products. Unfortunately, this bounty of structures remains untapped. Decades of research has realized only one GAG-like synthetic, small-molecule drug, fondaparinux. This represents an abysmal output because GAGs present a frontier that few medicinal chemists, and even fewer pharmaceutical companies, dare to undertake. GAGs are heterogeneous, polymeric, polydisperse, highly water soluble, synthetically challenging, too rapidly cleared, and difficult to analyze. Additionally, GAG binding to proteins is not very selective and GAG-binding sites are shallow. This Perspective attempts to transform this negative view into a much more promising one by highlighting recent advances in GAG mimetics. The Perspective focuses on the principles used in the design/discovery of drug-like, synthetic, sulfated small molecules as allosteric modulators of coagulation factors, such as antithrombin, thrombin, and factor XIa. These principles will also aid the design/discovery of sulfated agents against cancer, inflammation, and microbial infection.

Verifying the role of 3-hydroxy of 17-cyclopropylmethyl-4,5α-epoxy-3,14ß-dihydroxy-6ß-[(4'-pyridyl) carboxamido]morphinan derivatives via their binding affinity and selectivity profiles on opioid receptors.

In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [35S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.

Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry.

A bivalent compound 1a featuring both a mu opioid receptor (MOR) and a CXCR4 antagonist pharmacophore (naltrexone and IT1t) was designed and synthesized. Further binding and functional studies demonstrated 1a acting as a MOR and a CXCR4 dual antagonist with reasonable binding affinities at both receptors. Furthermore, compound 1a seemed more effective than a combination of IT1t and naltrexone in inhibiting HIV entry at the presence of morphine. Additional molecular modeling results suggested that 1a may bind with the putative MOR-CXCR4 heterodimer to induce its anti-HIV activity. Collectively, bivalent ligand 1a may serve as a promising lead to develop chemical probes targeting the putative MOR-CXCR4 heterodimer in comprehending opioid exacerbated HIV-1 invasion.

Synthetic Strategies to Diverse Polyquinanes via Olefin Metathesis: Access to the Basic Core of Crinipellin, Presilphiperfolanol, and Cucumin.

A rapid and useful synthetic approach to various polyquinane-based natural products was accomplished efficiently by employing ring-rearrangement metathesis and ring-closing metathesis as key steps. Here, we report the synthesis of stereochemically well-defined cis-anti-cis triquinanes (1, 2), tetraquinanes (3, 4), a novel pentaquinane 5, and fused [5-5-5-6] tetracyclic systems (6, 7) that are present in crinipellin, presilphiperfolanol, cucumin, etc. Hence, the current strategy may be suitable for the synthesis of various complex natural and unnatural cyclopentanoid targets. Moreover, our approach to the newly synthesized pentaquinane 5 has paved the way for various complex polyquinanes/molecules having significant applications in theoretical and medicinal chemistry.

Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement Metathesis.

Herein, a facile synthesis of intricate fused N-heterocycles is disclosed by employing C-H activation and ring-rearrangement metathesis/enyne ring-rearrangement metathesis as key steps. Interestingly, some of these N-heterocyclic products possess the tricyclic core of epimeloscine, deoxycalyciphylline B, daphlongamine H, isodaphlongamine H, and a bioactive alkaloid, annotinolide A, which shows antiaggregation activity against amyloid-ß (Aß)1-42 peptide aggregation. Moreover, various starting materials required in this protocol are easily assembled via C-X bond annulation of 2-bromo-N-protected aniline with norbornadiene or directing group-assisted ruthenium-catalyzed C-H activation of N-methoxybenzamide.

Bridgehead vicinal diallylation of norbornene derivatives and extension to propellane derivatives via ring-closing metathesis.

Here, we report a simple synthetic strategy to the bridgehead vicinal diallylation of norbornene derivatives. These substrates are useful to generate propellanes via ring-closing metathesis. Single-crystal X-ray diffraction analysis of four compounds led to the realization of configurational correction of earlier reported molecules.

Design and synthesis of propellane derivatives and oxa-bowls via ring-rearrangement metathesis as a key step.

Various intricate propellane derivatives and oxa-bowls have been synthesized via a ring-rearrangement metathesis (RRM) as a key step starting from readily accessible starting materials such as p-benzoquinone, 1,4-naphthoquinone and 1,4-anthraquinone.

Design and synthesis of polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis as key steps.

Here, we describe a new and simple synthetic strategy to various polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis (RRM) as the key steps. This approach delivers tri- and tetracyclic sulfones with six (n = 1), seven (n = 2) or eight-membered (n = 3) fused-ring systems containing trans-ring junctions unlike the conventional all cis-ring junctions generally obtained during the RRM sequence. Interestingly the starting materials used are simple and commercially available.

Crystal structure of 1,3-diallyl-1,3,3a,4,7,7a-hexa-hydro-4,7-methano-2-benzo-thio-phene 2,2-dioxide.

The title compound C15H20O2S, was identified as a product of di-allyl-ation of the meso-isomer of the corresponding norbornene sulfone, and it is an achiral compound. The five-membered heterocycle adopts an envelope conformation with the S atom deviating by 0.795 (3) Šfrom the other atoms of the ring (r.m.s. deviation = 0.0131). Both allyl groups are anti-oriented relative to the S atom but their double bonds are directed in opposite directions relative to the plane of the heterocycle.