Design, Synthesis, and Evaluation of Allosteric Effectors for Hemoglobin.

Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in hemoglobin (Hb), the protein in the red blood cell (RBC) responsible for the transport of oxygen (O2) throughout the body. The mutation leads to the expression of sickle cell hemoglobin (HbS). Both Hb and HbS exist in equilibrium between oxygenated and deoxygenated forms; however, deoxygenated HbS can polymerize to form long fibers which distort the shape of RBCs into the characteristic sickled shape. The misshapen RBCs can obstruct blood vessels and capillaries, resulting in a vaso-occlusive crisis. Vaso-occulsion deprives tissues and organs of O2 and can cause intense pain which often results in hospitalization. Chronic organ damage is a major cause of reduced life expectancy for SCD patients.Allosteric effectors are molecules which regulate protein function. HbS allosteric effectors can be used to decrease polymerization by stabilizing the oxygenated form of HbS, which leads to an increase in O2 uptake and a decrease in the sickling of RBCs. Allosteric effectors that have been evaluated for the treatment of SCD include vanillin, 5-hydroxymethyl furfural (5-HMF), and voxelotor, which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of SCD in 2019. 5-HMF did not progress to phase III clinical trials since it suffered from rapid metabolic degradation. However, several derivatives of 5-HMF and vanillin have been synthesized and evaluated as potential candidates for SCD treatment. Derivatives of these compounds have shown promise, but their shortcomings, such as high levels of oxidative metabolism, have prevented them from progressing into marketable drugs. Our efforts have produced multiple 5-HMF derivatives which have been evaluated for their potential to treat SCD. Each derivative was evaluated for its ability to increase O2 affinity (i.e., P50, the partial pressure at which hemoglobin is 50% saturated with O2). The synthesized aryl ether derivatives were evaluated, and results suggest that compounds with multiple aromatic aldehydes may have enhanced biological properties. One such derivative, compound 5, which features two furan aldehyde rings, exhibited increased O2 affinity (P50 = 8.82 ± 1.87 mmHg) over that of unmodified Hb (P50 = 13.67 ± 0.22 mmHg). Future studies include obtaining crystal structures of the 5-HMF derivatives complexed with HbS to confirm the protein-allosteric effector interactions.

Distorted zinc coordination polyhedra in bis-(1-eth-oxy-2-{[(2-meth-oxy-eth-yl)imino]-meth-yl}propan-1-olato)zinc, a possible CVD precursor for zinc oxide thin films.

A new metal-organic precursor for the chemical vapor deposition of zinc oxide thin films, [Zn(C9H16NO3)2], has been synthesized and characterized by 1H and 13C NMR spectroscopy, single-crystal X-ray diffraction and thermogravimetric analysis. The asymmetric unit of the title compound consists of two mol-ecules (Z' = 2), with different zinc coordination polyhedra. In one mol-ecule, the metal atom is in a distorted trigonal-bipyramidal ZnN2O3 environment (τ5 = 0.192) with a long bond to an ether O donor atom [Zn-O = 2.727 (6) Å]. In the other, the Zn atom is in a distorted ZnN2O4 octa-hedral environment with long bonds to the ether O donors of both ligands [Zn-O = 2.514 (4) and 2.661 (4) Å; O-Zn-O = 82.46 (14)°]. The crystal structure features weak C-H⋯·O inter-actions.

Bis[methyl 3-(propyl-amino)-but-2-eno-ato]zinc.

The title compound, [Zn(C(8)H(14)NO(2))(2)], represents a zinc complex with the Zn(2+) cation coordinated by two O and two N atoms in a distorted tetrahedral geometry.

Synthesis and characterization of zinc AP-MOCVD precursors and their utility in the growth of ZnO.

A novel beta-ketoimine, 4-N-(n-butylamino)-3-penten-2-one (1), and beta-enaminoester, Ethyl 3-N-(isopropylamino)-2-butenoate (2), were synthesized by the reaction of the 2,4-pentanedione or ethyl 3-oxo butanoate with the n-butyl and isopropyl amine, respectively. The isolated free ligands 1 and 2 were reacted with diethylzinc to afford Zn(CH3C(NCH2CH2CH2CH3)CHCOCH3)2 (3) and Zn(CH3C(NCH(CH3)2)CHC(O)OCH2CH3)2 (4) respectively. The isolated zinc complexes, 3 and 4, were characterized by elemental analysis, NMR, and MALDI-TOFMS. The molecular structure of 3 and 4 were determined via single crystal X-ray diffraction which revealed both compounds to be four coordinate, monomeric and homoleptic in the solid state. TG analysis showed the air stable compounds to be thermally robust as they both sublimed in a one-step process at atmospheric pressure. The compounds were utilized in the growth of ZnO via AP-MOCVD in the absence of additional oxidant. The carbon content of the film grown from 3 as determined by XPS was 26.2% while that of the film grown by 4 was 8.71%.