Studies on the mechanism of antimalarial action of a novel arylene bis(methylketone)

CT-guided neurolytic splanchnic nerve block is a technique for relieving abdominal cancer pain; the goal is the alcoholic neurolytic interruption of the sensitive structures in retroperitoneal space. CT yields accurate anatomical detailing and the course for needle placement and alcohol spread. January, 1993, to July, 1996, twenty-one bilateral splanchnic nerve blocks were performed through the posterior access. Forty-eight hours after alcoholization, 14 patients (66%) had complete pain regression; 52% of the patients needed no analgesics for 6 to 54 days and only 9 patients (42%) needed another low opioid therapy. Complications included hypotension and diarrhea in all cases. One had a cardiac arrest and died 8 days after the procedure. There were no other complications. The whole procedure usually lasted 60 min (range: 45 to 90 min). Splanchnic nerve neurolysis is a useful treatment in the patients with severe chronic abdominal pain. It is used as a second line treatment when large lesions change celiac anatomy and complicate the percutaneous block of the celiac plexus.     

Antimalarial activity of synthetic analogues of distamycin

Malaria, one of the most serious diseases transmitted by arthropods, is largely present in tropical and even temperate zones in endemic or epidemic form. More than 40% of the world's population lives in areas at risk for exposure, and the World Health Organization reports that approximately 300 million people are affected by the infection (mostly caused by the species Plasmodium falciparum), with 1-2 million deaths per year. These data, and the fact that malaria is becoming increasingly refractory to treatment through resistance of the parasite to antimalarial agents currently in use, e.g., chloroquine, emphasize the need to develop new drugs. The well-known antiparasitic activity of oligopyrrolamidine natural products, such as distamycin and netropsin, suggested the antimalarial evaluation of related compounds obtained by new chemical modifications. Besides possessing antiviral and antitumoural properties, distamycin exhibits interesting in vitro activity against P. falciparum. Unfortunately, the high toxicity associated with this product precludes its development as a drug. However, some synthetic analogues of distamycin proved to be highly active against chloroquine-sensitive and -resistant strains of P. falciparum, besides showing low toxicity in vitro.     

DNA-Directed alkylating agents. 7. Synthesis, DNA interaction, and antitumor activity of bis(hydroxymethyl)- and bis(carbamate)-substituted pyrrolizines and imidazoles

A series of bis(hydroxymethyl)-substituted imidazoles, thioimidazoles, and pyrrolizines and related bis(carbamates), linked to either 9-anilinoacridine (intercalating) or 4-(4-quinolinylamino)benzamide (minor groove binding) carriers, were synthesized and evaluated for sequence-specific DNA alkylation and cytotoxicity. The imidazole and thioimidazole analogues were prepared by initial synthesis of [(4-aminophenyl)alkyl]imidazole-, thioimidazole-, or pyrrolizine dicarboxylates, coupling of these with the desired carrier, and reduction to give the required bis(hydroxymethyl) alkylating moiety. The pyrrolizines were the most reactive alkylators, followed by the thioimidazoles, while the imidazoles were unreactive. The pyrrolizines and some of the thioimidazoles cross-linked DNA, as measured by agarose gel electrophoresis. Strand cleavage assays showed that none of the compounds reacted at purine N7 or N3 sites in the gpt region of the plasmid gpt2Eco, but the polymerase stop assay showed patterns of G-alkylation in C-rich regions. The corresponding thioimidazole bis(carbamates) were more selective than the bis(hydroxymethyl) pyrrolizines, with high-intensity bands at 5'-NCCN, 5'-NGCN and 5'-NCGN sequences in the PCR stopping assay ( indicates block sites). The data suggest that these targeted compounds, like the known thioimidazole bis(carbamate) carmethizole, alkylate exclusively at guanine residues via the 2-amino group, with little or no alkylation at N3 and N7 guanine or adenine sites. The cytotoxicities of the compounds correlated broadly with their reactivities, with the bis(hydroxymethyl)imidazoles being the least cytotoxic (IC50s >1 microM; P388 leukemia) and with the intercalator-linked analogues being more cytotoxic than the corresponding minor-groove-targeted ones. This was true also for the more reactive thioimidazole bis(carbamates) (IC50s 0.8 and 11 microM, respectively), but both were more active than the analogous "untargeted" carmethizole (IC50 20 microM). The bis(hydroxymethyl)pyrrolizine analogues were the most cytotoxic, with IC50s as low as 0.03 microM.     

Synthesis and biological activity of bis(pivaloyloxymethyl) ester of 2'-azido-2'-deoxyuridine 5'-monophosphate

Bis(pivaloyloxymethyl) ester of 2'-azido-2'-deoxyuridine 5'-monophosphate was prepared as a prodrug to generate 2'-azido-2'-deoxyuridine 5'-diphosphate inside the cell. A synthetic route utilizing stannyl phosphate was adopted in the preparation. The prodrug was evaluated for cell growth inhibition against a variety of tumor cell lines along with 2'-azido-2'-deoxyuridine and 2'-azido-2'-deoxycytidine.     

A novel extractant bis(2-ethylhexyl) ((2-ethylhexylamino)methyl) phosphine oxide for cerium(IV) extraction and separation from sulfate medium

By introducing the amine group into phosphorus extractant, a novel aminophosphine compound bis(2-ethylhexyl) ((2-ethylhexylamino)methyl) phosphine oxide (DEHAPO, abbreviated as A) was synthesized for the extraction of cerium (IV) (Ce(IV)) from sulfate medium (H₂SO₄). The influence factors including extractant concentration, H₂SO₄ concentration and temperature on the Ce(IV) extraction were investigated and discussed. It is found that the extraction ability of Ce(IV), thorium (IV) (Th(IV)) and rare earths (REs(III)) (La, Gd, Yb) decreases in sulphate medium in the following order: Ce(IV) > Th(IV) > REs(III). The extraction process is an exothermic reaction and the thermodynamic parameters were calculated. The extracted complex of Ce(HSO₄)₂SO₄·A in loaded organic solution was identified by the slope methods and further proved by FT-IR spectral analysis. Stripping studies indicate that Ce(IV) can be effectively stripped from the organic phase. The results of separation factors (β) and saturation loading capacity demonstrate that DEHAPO could be used to selectively extract Ce(IV) from sulphate medium with high separation efficiency and good extraction ability.     

The chemotherapy of rodent malaria, XXV. Antimalarial activity of WR 122,455 (a 9-phenanthrenemethanol) in vivo and in vitro

WR 122,455, 3,6-bis-(trifluoromethyl)-alpha-(2-piperidinyl)-9-phenanthrenemethanol HCl, suppresses infection with drug-sensitive Plasmodium berghei N strain in mice. It acts rapidly and affects all the stages of the asexual intraerythrocytic parasites, the effective dose levels being about three times those of chloroquine and one-twelfth to one-fifteenth those of quinine. Under the influence of WR 122,455 haemozoin seems to disappear from the affected parasites following an initial coarsening of the fine pigment granules. These changes are similar to those exerted by quinine. Large doses of WR 122,455 have a residual affect due in part, at least, to deposition of insoluble material in the tissues. The drug appears to exert an antagonistic action on chloroquine when both drugs are administered simultaneously. It has no causal prophylactic effect. In vitro WR 122,455 is a competitive antagonist of chloroquine in a similar manner to quinine, and appears to have a dissociation constant (Ki) of 2-26 x 10(-8) M, making it about 18 times as active as quinine. WR 122,455 interacts strongly with calf thymus DNA, but the mechanism of interaction has yet to be defined. Mice tolerate single doses of a saline/Tween 80 suspensions up to about 400 mg/kg but sc administration induces necrotic changes at the injection site. Up to 30 mg/kg daily po for seven consecutive days is well tolerated systemically but local tissue reaction may occur if the drug is given by the sc or ip routes. However, systemically up to 60 mg/kg is tolerated sc or ip. The relation of WR 122,455 to drug resistant malaria will be reported later.     

Peptide inhibitors of N-succinyl diaminopimelic acid aminotransferase (DAP-AT): a novel class of antimicrobial compounds

Dipeptide substrates of N-Succinyl Diaminopimelic Acid Aminotransferase (DAP-AT) were converted to hydrazines by treatment with hydrazine and cyanoborohydride. These compounds were tested in vitro as inhibitors of DAP-AT from E. coli and in vivo as antibiotics. The hydrazino-dipeptides showed potent slow binding slow binding inhibition of DAP-AT as well as antimicrobial activity.     

Extraction of molybdenum with bis(2,4,4-trimethylpentyl)phosphine acid (Cyanex-272)

The influence of different parameters on the recovery of molybdenum by extraction with bis(2,4,4-trimethylpentyl)phosphine acid (Cyanex-272) is considered. It is established that its maximum value is attained at pH ∼2. Using the methods of saturation and the shift of the equilibrium, it is shown that Cyanex-272 extracts Mo from hydrochloric, nitric, and sulfuric acid solutions by the mechanism of the cation exchange with the attachment of two single-charged acidic residues of the dimer of bis(2,4,4-trimethylpentyl)phosphine acid to the molybdenum cation. Based on the data obtained by UV and IR spectroscopy, the structure of the extracted molybdenum compounds is determined. It is shown that it is similar to the structure of the substances that form during extraction using other organophosphorous acids.     

Synthesis and antitumor activity of 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates

Ten 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates were synthesized and evaluated for antitumor activity. The 2-phenoxyethyl ester exhibited activity against P-388 lymphocytic leukemia, and the n-butyl and n-pentyl esters exhibited activity against L-1210 lymphoid leukemia in initial screening tests.     

Colony promoting activity (CPA) is a novel factor distinct from IL-6

The supernatant (CM) of long-term bone marrow culture (LTBMC) contains colony promoting activity (CPA) which does not have granulocyte-macrophage (GM) colony-stimulating activity but which enhances GM-colony formation in the presence of CSF. CPA is different from IL-1, IL-3 and GM, G-, and M-CSF. Since CPA-containing LTBMC-CM always contains a substantial level of IL-6, CPA was thought to be similar to IL-6. In the present study, we found that LTBMC with a particular batch of horse serum produced IL-6 without a corresponding production of CPA. Addition of IL-6 to GM-colony assay system in the presence of GM-CSF did not enhance the colony formation. LTBMC-CM did not stimulate proliferation nor differentiation of mast cell progenitors. Anti-IL-6 antibodies suppressed IL-6 activity, but not CPA. These results indicate that CPA is a novel factor distinct from IL-1, IL-3, G-, M-, GM-CSF, IL-6 and SCF (c-kit ligand).     

Bisquinolines. 2. Antimalarial N,N-bis(7-chloroquinolin-4-yl)heteroalkanediamines

N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were significantly more potent against the chloroquine-resistant W2 clone compared to the chloroquine-sensitive D6 clone. For bisquinolines 1-11 there was no relationship between the length of the bisquinoline heteroalkane bridge and antimalarial activity and no correlation between in vitro and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquinolines with alkylamine bridges against P. berghei in vivo. Bisquinolines 1-10 were potent inhibitors of hematin polymerization with IC50 values falling in the narrow range of 5-20 microM, and there was a correlation between potency of inhibition of hematin polymerization and inhibition of parasite growth. Compared to alkane-bridged bisquinolines (Vennerstrom et al., 1992), none of these heteroalkane-bridged bisquinolines had sufficient antimalarial activity to warrant further investigation of the series.     

New compounds: antitumor activity of 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrate

3beta-Hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam 4-[p[bis(2chloroethyl)amino]phenyl]butyrate was prepared by reacting 4-[p-[bis(2-chloroethyl)amino]phenyl]butyryl chloride hydrochloride with 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam. They cytostatic action of the ester was investigated on two tumor systems (B16 melanoma on C57 b1 mice and T8-Guerin on rats).     

Condensed heterocyclic compounds: synthesis and antiinflammatory activity of novel thiazolo[3,2-alpha] pyrimidines

In this study, thirty six new 2-benzylidene-7-methyl-3-oxo-5- phenyl-2,3-dihydro-5H-thiazolo[3,2-alpha]pyrimidine-6-carboxylic acid methyl esters were synthesized and characterized by spectral, crystallographic, and elemental analysis. The antiinflammatory activity of the compounds was tested by the carrageenan hind paw edema test. It was found that compound 6a having a 2-meth-oxyphenyl group at position 5 and a benzylidene group at position 2 was the most potent compound in this series. All the compounds that were tested for ulcer activity gave positive results.