Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for Malaria and Leishmaniasis

Abstract

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC(50) values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.

Total syntheses of (±)-ovalicin, C4(S∗)-isomer, and its C5-analogs and anti-trypanosomal activities

“…As shown in the analog synthesis, the stereochemistry at C6 (R*-configuration) of 2 is crucial for the generation of the correct stereochemistry at C4 of ovalicin in the addition reaction with the alkenyllithium (vide infra). Monomethylation of diol 13 with Me 3 O•BF 4 and proton sponge led to an 81% yield of methyl ether 19 and 20 in a ratio of 1.2:1 along with a small amount (6% yield) of the dimethoxylated product. Other methylation reactions were attempted such as the uses of methyl iodide or methyl triflate and sodium hydride or amine bases resulted in no methylation product.…”

“…Epoxidation of 31 with MCPBA-NaF-KF in dichloromethane 19 gave epoxides 32 and 33 in a 1:1 ratio, which decomposed slowly on silica gel column. The crude mixture of 32 and 33 was subjected to the dihydroxylation conditions, OsO 4 and NMO, to give a 46% overall yield of diols 34, 35, and 36 in a ratio of 5:4:1, which were separated by silica gel column chromatography. The relative stereochemistry of a major product, diol 34, was established from a single-crystal Xray analysis of its C5-monosilyl ether derivative, 37, from the silylation reaction with tbutyldimethylsilyl chloride and triethylamine (Figure 1).…”

“…After stirring at 40 °C for 15 min, the solution was diluted with diethyl ether, washed with aqueous NH 4 Cl, aqueous NaHCO 3 , water, and brine, dried (MgSO 4 ), concentrated, and column chromatographed on silica gel using a mixture of hexane and diethyl ether …”

“…Stereochemistry of 36 was determined from a NMR 2D NOESY experiment. 4 , and the solution was stirred at 0 °C for 7 h. To it, 20 mg (0.14 mmol) of Me 3 O•BF 4 was added, and the solution was stirred at 0 °C for 1.5 h, diluted with diethyl ether, washed with 1 N HCl, aqueous sodium dicarbonate, and brine, dried (MgSO 4 ), concentrated, and column chromatographed on silica gel using a mixture of hexane and ethyl acetate (3:2) as eluant to give 93 mg (46% yield) of compound 38 and 69 mg (34% yield) of 39. , 1 H), 2.68 (bs, 1 H), 2.27 (s, 1 H), 2.07 -1.97 (m, 2 H), 1.72 (s, 3 H), 1.69 (s, 3 H 4S*,5S*)-4-Hydroxy-5-methoxy-4-[(E)-(1',5'-dimethylhexa-1',4'-dienyl) (3S*,4S*,5R*,6S*)-4-Methoxy-5-[(E)-(1',5'-dimethylhexa-1',4'-dienyl)--6-(tertbutyldimethylsilyloxy)-1-oxaspiro[…”

“…Fumagillin, structurally similar to ovalicin, has been shown to inhibit methionine aminopeptidase 2 (MetAP2) leading to anti-angiogenesis. 4 Since MetAP2 presents in parasites, 4 syntheses and studies of antitrypanosomal activities of ovalicin and its analogs were undertaken. Several total syntheses of ovalicin have appeared starting from functionalized six-membered ring compounds, 6-11 but an acyclic starting material is rare.…”