Biomedical subjects
Publications and source records attributed to Ming Xian.
The [1,5]-Brook rearrangement proceeds efficiently in a series of hydroxyl dithiane substrates with sodium and potassium bases; less effective are lithium bases. That the mode of silyl migration is intramolecular was demonstrated by a crossover experiment. Finally, the tricomponent anion relay chemistry (ARC) coupling tactic was demonstrated employing the [1,5]-Brook rearrangement.
An effective one-flask multicomponent linchpin coupling protocol employing the concept of anion relay chemistry (ARC) was developed. This concept calls for addition of an anion (5) to an epoxide (6), bearing on a distal carbon a trialkyl silyl group and an anion stabilizing group (ASG), to furnish upon epoxide ring opening oxyanion 7. Addition of HMPA or other polar solvents to trigger a solvent controlled 1,4-Brook rearrangement then leads to a new distal anion (8), which in turn is available to react with a variety of second electrophiles.
[structure: see text] The design, synthesis, and biological evaluation of seven totally synthetic analogues of the antitumor agent (+)-discodermolide are reported. Saturation of the terminal diene system, alteration of the substituents on the lactone, and alkylation of the C7-hydroxyl group reveal significant structure-activity relationships.
[structure: see text] The design, total synthesis, and biological evaluation of two C13-C14-cyclopropyl analogues [(+)-1 and (+)-2] of (+)-discodermolide have been achieved. Key features of the syntheses include highly stereoselective, hydroxyl-directed cyclopropanations of vinyl iodides and higher order cuprate-mediated cross-coupling reactions between cyclopropyl iodides and alkyl iodides. Biological evaluation revealed that neither orientation of the cyclopropyl methylene completely substitutes for the C14 methyl found in (+)-discodermolide (3).
A series of simplified discodermolide analogues have been designed and synthesized in an attempt to understand the role of the lactone ring. These synthetic efforts have led to an unsubstituted butyrolactone 9 being generated, which shows improved activity over the natural product.
[structure: see text] A highly convergent, fourth-generation total synthesis of (+)-discodermolide (1), with a longest linear sequence of 17 steps and an overall yield of 9.0%, has been achieved. Highlighting the strategy is the efficient construction and sequential, bidirectional union of a linchpin comprising the C(9)-C(14) Wittig salt-vinyl iodide (-)-18. Importantly, Wittig salt generation proceeded in excellent yield under ambient pressure.
Geldanamycin (GA) is a potent anticancer antibiotic that inhibits Hsp90. Its potential clinical utility is hampered by its severe toxicity. To alleviate this problem, we synthesized a series of carbohydrate-geldanamycin conjugates for enzyme-specific activation to increase tumor selectivity. The conjugation was carried out at the C-17-position of GA. Their anticancer activity was tested in a number of cancer cell lines. The enzyme-specific activation of these conjugates was evaluated with beta-galactosidase and beta-glucosidase. Evidently, glycosylation of C-17-position converted GA to an inactive prodrug before enzyme cleavage. Glucose-GA, as positive control, showed anticancer activity with IC(50) of 70.2-380.9 nM in various cancer cells by beta-glucosidase activation inside of the tumor cells, which was confirmed by 3-fold inhibition using beta-glucosidase specific inhibitor [2,5-dihydroxymethy-3,4-dihydroxypyrrolidine (DMDP)]. Compared to glucose-GA, galactose- and lactose-GA conjugates exhibited much less activity with IC(50) greater than 8000-25 000 nM. However, when galactose- and lactose-GA were incubated with beta-galactosidase in the cells, their anticancer activity was enhanced by 3- to 40-fold. The results suggest that GA can be inactivated by glycosylation of C-17-position and reactivated for anticancer activity by beta-galactosidase. Therefore, galactose-GA can be exploited in antibody-directed enzyme prodrug therapy (ADEPT) with beta-galactosidase for enzyme-specific activation in tumors to increase tumor selectivity.
[Structure: see text] The design, syntheses, and biological evaluation of 22 totally synthetic analogues of the potent microtubule-stabilizing agent (+)-discodermolide (1) have been achieved. Structure-activity relationships of the C(19) carbamate were defined, exploiting two synthetically simplified scaffolds, as well as the parent (+)-discodermolide framework.
[Structure: see text] The design, syntheses, and biological evaluation of nine totally synthetic analogues of the microtubule-stabilizing agent (+)-14-normethyldiscodermolide (2) are reported. Simplification at the C(21)-C(24) terminal diene and at the C(1)-C(5) lactone moieties reveals significant structure-activity relationships.
Hemoglobin (Hb) is an oligomeric protein, composed of four monomeric subunits. Hb molecule may undergo dissociation from a single native tetramer to two dimmers, which is called hemoglobin dissociation. In this article the dissociation of bovine Hb is studied by measurment of the average MW of the samples using the multiangle laser light-scattering method. Advanced multiangle laser light-scattering technique is a powerful method to determine the absolute molecular weights of the protein in solution. Two different methods, microbatch multiangle light-scattering (MALS) and on-line size-exclusion high-performance liquid chromatography light scattering with refractive index detector, are used to measure the average molecular weight of bovine Hb in different concentration respectively. The results of the two methods are agreed well. From the results, it can be concluded that the average molecular weigh of bovine Hb will be about 54 kDa when the bovine Hb concentration is more than 1.5 mg/mL, and will be about 36 kDa when the concentration is less than 0.03 mg/mL. The other conclusion, which can be derived from these results, is that the dissociation of bovine Hb is related with the pH and the tetramer appears to be more stable in the pH range of 6-9.
Because of the double-edged nature of NO, the development of isoform-selective NOS substrates is a highly desirable goal. Given the striking similarity in the heme active sites of the three NOS isoforms, it presents an challenging problem. Several N-aryl-N'-hydroxyguanidines have recently been shown as substrates that are selective for iNOS over nNOS. Here, we report the first success that 3 is a good substrate for nNOS (70% activity of NOHA, K(m) approximately 40 +/- 6 microM) over iNOS.
A series of N-alkyl-N'-hydroxyguanidine compounds have recently been characterized as non-amino acid substrates for all three nitric oxide synthase (NOS) isoforms which mimic NO formation from N(omega)-hydroxy-L-arginine. Crystal structures of the nNOS heme domain complexed with either N-isopropyl-N'-hydroxyguanidine or N-butyl-N'-hydroxyguanidine reveal two different binding modes in the substrate binding pocket. The binding mode of the latter is consistent with that observed for the substrate N(omega)-hydroxy-L-arginine bound in the nNOS active site. However, the former binds to nNOS in an unexpected fashion, thus providing new insights into the mechanism on how the hydroxyguanidine moiety leads to NO formation. Structural features of substrate binding support the view that the OH-substituted guanidine nitrogen, instead of the hydroxyl oxygen, is the source of hydrogen supplied to the active ferric-superoxy species for the second step of the NOS catalytic reaction.
The electrochemical properties of a series of N-substituted-N'-hydroxyguanidines were studied. Two oxidation potentials of each compound were obtained by cyclic voltammetry. The E(ox1) values were from 0.51 to 0.62V, while the E(ox2) values were from 1.14 to 1.81V in acetonitrile solution. Next, their enzymatic controlled NO release abilities were evaluated. All N'-hydroxyguanidines exhibited efficient NO release abilities under the oxidation by horseradish peroxidase in the presence of H(2)O(2).
A series of mannose conjugated S-nitroso-N-acetylpenicillamines (SNAPs) has been synthesized, and their cytotoxicities were assessed for DU 145 human prostate cancer cells and Hela R cancer cells.
Enzymatic generation of nitric oxide (NO) by nitric oxide synthase (NOS) consists of two oxidation steps. The first step converts L-arginine to N(G)-hydroxy-L-arginine (NOHA), a key intermediate, and the second step converts NOHA to NO and L-citrulline. To fully probe the substrate specificity of the second enzymatic step, an extensive structural screening was carried out using a series of N-alkyl (and N-aryl) substituted-N'-hydroxyguanidines (1-14). Among the eleven N-alkyl-N'-hydroxyguanidines evaluated, N-n-propyl (2), N-iso-propyl (3), N-n-butyl (4), N-s-butyl (5), N-iso-butyl (6), N-pentyl (8) and N-iso-pentyl (9) derivatives were efficiently oxidized by the three isoenzymes of NOS (nNOS, iNOS and eNOS) to generate NO. N-Butyl-N'-hydroxyguanidine (4) was the best substrate for iNOS (K(m)=33 microM) and N-iso-propyl-N'-hydroxyguanidine (3) was the best substrate for nNOS (K(m)=56 microM). When the alkyl substituents were too small (such as ethyl 1) or too large (such as hexyl 10 and cyclohexyl 11), the activity decreased significantly. This suggests that the van der Waals interaction between the alkyl group and the hydrophobic cavity in the NOS active site contributes significantly to the relative reactivity of compounds 3-11. Moreover, five N-aryl-N'-hydroxyguanidines were found to be good substrates for iNOS, but not substrates for eNOS and nNOS. N-phenyl-N'-hydroxyguanidine was the best substrate among them (K(m)=243 microM). This work demonstrates that N-alkyl substituted hydroxyguanidine compounds are novel NOS substrates which 'short-circuit' the first oxidation step of NOS, and N-aryl substituted hydroxyguanidine compounds are isoform selective NOS substrate.
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A general methodology has been established for rapid generation and screening of combinatorial glycopeptide library and subsequent mass spectrometric sequencing to identify the mimetics of Galalpha(1,3)Gal epitopes. Using this approach, several active glycopeptide sequences were recognized and found to inhibit the binding of human natural anti-Gal antibodies with comparable IC(50)s to synthetic Galalpha(1,3)Gal oligosaccharides. The most active glycopeptides detected from the library included Gal-Tyr-Trp-Arg-Tyr, Gal-Thr-Trp-Arg-Tyr, and Gal-Arg-Trp-Arg-Tyr. These glycopeptides showed higher affinities to anti-Gal antibodies than known Galalpha(1,3)Gal peptide mimetics, such as DAHWESWL and SSLRGF. Our results suggest that, by combining a peptide sequence (the "functional" mimic part) with a terminal alpha-linked galactose moiety (the "structural" mimic part), the resulting glycopeptide could be a very good Galalpha(1,3)Gal mimetic. Analysis of these active glycopeptides provided first-hand information regarding the binding site of anti-Gal antibodies to facilitate the structurally based design of more potent and stable inhibitors.