Enzyme Control Over Ferric Iron Magnetostructural Properties.

Fe3+ complexes in aqueous solution can exist as discrete mononuclear species or multinuclear magnetically coupled species. Stimuli-driven change to Fe3+ speciation represents a powerful mechanistic basis for magnetic resonance sensor technology, but ligand design strategies to exert precision control of aqueous Fe3+ magnetostructural properties are entirely underexplored. In pursuit of this objective, we rationally designed a ligand to strongly favor a dinuclear µ-oxo-bridged and antiferromagnetically coupled complex, but which undergoes carboxylesterase mediated transformation to a mononuclear high-spin Fe3+ chelate resulting in substantial T1 -relaxivity increase. The data communicated demonstrate proof of concept for a novel and effective strategy to exert biochemical control over aqueous Fe3+ magnetic, structural, and relaxometric properties.

Cytotoxic Naphthoquinone Analogues, Including Heterodimers, and Their Structure Elucidation Using LR-HSQMBC NMR Experiments.

Approximately 1700 naphthoquinones have been reported from a range of natural product source materials, but only 283 have been isolated from fungi, fewer than 75 of those were dimers, and only 2 were heterodimers with a head-to-tail linkage. During a search for anticancer leads from fungi, a series of new naphthoquinones (1-4), including two heterodimers (3 and 4), were isolated from Pyrenochaetopsis sp. (strain MSX63693). In addition, the previously reported 5-hydroxy-6-(1-hydroxyethyl)-2,7-dimethoxy-1,4-naphthalenedione (5), misakimycin (6), 5-hydroxy-6-[1-(acetyloxy)ethyl]-2,7-dimethoxy-1,4-naphthalenedione (7), 6-ethyl-2,7-dimethoxyjuglone (8), and kirschsteinin (9) were isolated. While the structure elucidation of 1-9 was achieved using procedures common for natural products chemistry studies (high-resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D NMR), the elucidation of the heterodimers was facilitated substantially by data from the long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) experiment. The absolute configuration of 1 was established by analysis of the measured vs calculated ECD data. The racemic mixture of 4 was established via X-ray crystallography of an analogue that incorporated a heavy atom. All compounds were evaluated for cytotoxicity against the human cancer cells lines MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovarian), where the IC50 values ranged between 1 and 20 µM.

Rational Ligand Design Enables pH Control over Aqueous Iron Magnetostructural Dynamics and Relaxometric Properties.

Complexes of Fe3+ engage in rich aqueous solution speciation chemistry in which discrete molecules can react with solvent water to form multinuclear µ-oxo and µ-hydroxide bridged species. Here we demonstrate how pH- and concentration-dependent equilibration between monomeric and µ-oxo-bridged dimeric Fe3+ complexes can be controlled through judicious ligand design. We purposed this chemistry to develop a first-in-class Fe3+-based MR imaging probe, Fe-PyCy2AI, that undergoes relaxivity change via pH-mediated control of monomer vs dimer speciation. The monomeric complex exists in a S = 5/2 configuration capable of inducing efficient T1-relaxation, whereas the antiferromagnetically coupled dimeric complex is a much weaker relaxation agent. The mechanisms underpinning the pH dependence on relaxivity were interrogated by using a combination of pH potentiometry, 1H and 17O relaxometry, electronic absorption spectroscopy, bulk magnetic susceptibility, electron paramagnetic resonance spectroscopy, and X-ray crystallography measurements. Taken together, the data demonstrate that PyCy2AI forms a ternary complex with high-spin Fe3+ and a rapidly exchanging water coligand, [Fe(PyCy2AI)(H2O)]+ (ML), which can deprotonate to form the high-spin complex [Fe(PyCy2AI)(OH)] (ML(OH)). Under titration conditions of 7 mM Fe complex, water coligand deprotonation occurs with an apparent pKa 6.46. Complex ML(OH) dimerizes to form the antiferromagnetically coupled dimeric complex [(Fe(PyCy2AI))2O] ((ML)2O) with an association constant (Ka) of 5.3 ± 2.2 mM-1. The relaxivity of the monomeric complexes are between 7- and 18-fold greater than the antiferromagnetically coupled dimer at applied field strengths ranging between 1.4 and 11.7 T. ML(OH) and (ML)2O interconvert rapidly within the pH 6.0-7.4 range that is relevant to human pathophysiology, resulting in substantial observed relaxivity change. Controlling Fe3+ µ-oxo bridging interactions through rational ligand design and in response to local chemical environment offers a robust mechanism for biochemically responsive MR signal modulation.

Meroterpenoids from Neosetophoma sp.: A Dioxa[4.3.3]propellane Ring System, Potent Cytotoxicity, and Prolific Expression.

Six fungal metabolites, of which five were new, including one (1) with a dioxa[4.3.3]propellane ring system, were discovered, identified, and structurally elucidated from Neosetophoma sp. (strain MSX50044); these compounds are similar to the bis-tropolone, eupenifeldin. Three of the meroterpenoids are potent cytotoxic agents against breast, ovarian, mesothelioma, and lung cancer cells with nanomolar IC50 values while not inducing mitochondrial toxicity at 12.5 µM.

Total synthesis and absolute stereochemical assignment of kibdelone C.

Kibdelones are hexacyclic tetrahydroxanthones and potent anticancer agents isolated from an Australian microbe. Herein, we describe the synthesis of a chiral, nonracemic iodocyclohexene carboxylate EF ring fragment of the kibdelones employing an intramolecular iodo halo-Michael aldol reaction and its merger with an ABCD ring fragment to afford the congener kibdelone C.