Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis and biological activities of 12 analogs of N6-benzyladenosine are described. The compounds were prepared by two methods: (1) direct alkylation of adenosine with an appropriately substituted benzyl bromide to give the N1-substituted derivative which was then rearranged in base to give the N6-substituted compound, and (2) by nucleophilic displacement of chlorine in 6-chloropurine ribonucleoside, 6-chloro-2-aminopurine ribonucleoside, and 6-chloro-2-aminopurine with an amine. These analogs were examined for their growth inhibitory effect in cultured leukemic cells and also for their effect on adenosine aminohydrolase activity. N6-p-Nitrobenzyladenosine and its 2'-deoxy analog were competitive inhibitors (K1 65, 22 MUM). The 2-amino-N6-p-nitrobenzyladenine and its ribonucleoside were found to be noncompetitive inhibitors of adenosine aminohydrolase. In cultured L1210 leukemia, 2-amino-6-p-nitrobenzylaminopurine and the corresponding ribonucleoside were better growth inhibitors than N6-benzyladenosine, while N6-p-nitrobenzyladenosine, its 2'-deoxy analog, and N6-p-fluorobenzyladenosine were as active as N6-benzyladenosine.
 ...
PMID:Synthesis and biological activities of some N6-(nitro- and -aminobenzyl)adenosines. 105 53

Syntheses and biological activities of 26 N4-substituted 4-aminopyrazolo[3,4-d]pyrimidines as analogs of naturally occurring modified nucleic acid bases, N-(purin-6-ylcarbamoyl)-L-threonine and N6-(delta2-isopentenyl)adenine, are described. 4-Aminopyrazolo[3,4-d]pyrimidine was converted into the desired intermediate, ethyl pyrazolo[3,4-d]pyrimidine-4-carbamate (2). 4-Ureidopyrazolo[3,4-d]pyrimidines (6-26) were prepared by displacement of the ethoxy group of the carbamate 2 by amino acids and a variety of amines and by a reaction of 4-aminopyrazolo[3,4-d]pyrimidine (1) with isocyanates. N4-Alkylaminopyrazolo[3,4-d]pyrimidines were generally prepared by displacement of the chlorine from 4-chloropyrazolo[3,4-d]pyrimidine with various amines. Several analogs exhibited moderate to very good growth inhibitory activities against cultured L1210 leukemia and 6410 human leukemic myeloblasts.
 ...
PMID:Synthesis and biological activities of some N4-substituted 4-aminopyrazolo(3,4-d)pyrimidines. 106 72

More than 200 nitro compounds, most of them nitroaniline derivatives substituted with one or more radicals having a basic reaction, were prepared and investigated as to their therapeutic activity against bacteria, fungi, protozoa, helminths, viruses and tumors. Several mono-nitrobenzenes with a radical having a basic reaction showed weak in-vitro activity against gram-positive bacteria and against Crocker's sarcoma 180; they also showed systemic activity against nematodes (Aspiculuris tetraptera) and viruses. The majority of therapeutically active compounds with pronounced in-vivo activity against Trichomonas fetus, Entamoeba histolytica, Schistosoma mansoni, cestodes, nematodes (Ancylostoma caninum), viruses (influenza, MHV, SAV and EMC) and various types of carcinoma (Ehrlich's carcinoma, leukemia 1210, Crocker's sarcoma 180) were dinitrobenzene derivatives with one radical having a basic reaction and electropositive groups or unreactive or reactive chlorine atom, and di-nitrobenzene with two equal or two different radicals having a basic reaction. Compound No. 70 revealed a marked in-vitro activity against fungi (Trichophyton; Microsporum, Candida albicans). Other nitro compounds such as bis-mono- and bis-dinitrobenzene derivatives likewise showed a systemic action against E. histolytica, viruses and, in particular, carcinoma (Crocker's sarcoma 180, Ridgway's osteosarcoma). Oxygen and sulfur analogue compounds as well as compounds produced by reduction also possessed a distinct activity against E. histolytica and viruses. On the basis of the present results particularly the dinitrobenzenes substituted with two radicals having a basic reaction include a number which have in common that a structure/activity relationship is recognizable in respect of E. histolytica, Schistosoma mansoni and different types of viruses. The activity against viruses in this class of compounds is probably due to an increased interferon production in the host animal. Whether the mechanism of action is the same against E. histolytica or Schistosoma mansoni has not been determined so far. A tumorigenic effect was observed mainly in those di-nitrobenzenes which are classed as alkylating compounds. Because of the small chemotherapeutic index the trials were not continued with the most effective compounds mentioned.
 ...
PMID:[Chemotherapeutic effects of nitro compounds. 1. Nitroanilines]. 124 9

When grown in a defined medium containing 0.05% KBr, Saccharothrix aerocolonigenes ATCC 39243 produces a novel bromo analog of rebeccamycin. This new analog, designated bromorebeccamycin, has been isolated from the culture broth and purified by vacuum liquid chromatography and column chromatography. Spectroscopic data demonstrated that bromorebeccamycin has the same structure as rebeccamycin, except for the replacement of the two chlorine atoms by bromine atoms in the molecule. Bromorebeccamycin and rebeccamycin have a similar potency and activity against P388 leukemia in the murine model.
 ...
PMID:Isolation of a bromo analog of rebeccamycin from Saccharothrix aerocolonigenes. 193 15

The design and synthesis of (E)- and (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (6 and 13, respectively), a new class of mechanism-based inhibitors of S-adenosyl-L-homocysteine (SAH) hydrolase, is described. A number of analogues of 6 and 13 were synthesized in order to determine the structure-activity relationship necessary for inhibition of the enzyme. Substitution of chlorine for fluorine in 6 (i.e. 44), addition of an extra chlorine to the 5'-vinyl position (i.e. 51 and 52), modification of the 2'-hydroxyl group to the deoxy (34 and 35) and arabino (36 and 37) nucleosides provided competitive inhibitors of SAH hydrolase. Nucleosides 6 and 13, as well as 5'-deoxy-5',5'-difluoroadenosine (14) proved to be time-dependent inhibitors of SAH hydrolase. All three compounds are postulated to inhibit through the potent electrophile derived from oxidation of the 3'-hydroxyl of 6 or 13 to the ketone (i.e. 3 and/or the E-isomer). Consistent with the proposed mechanism of inactivation of SAH hydrolase by 6, 13, and 14 was the observation that incubation of purified rat liver SAH hydrolase with 6 resulted in release of 1 equiv of fluoride ion (by 19F NMR) and incubation with 14 resulted in release of 2 equiv of fluoride ion. The general synthetic route developed for the synthesis of the title nucleosides utilized the fluoro Pummerer reaction for the introduction of fluorine into the requisite precursors. Preliminary antiretroviral data from Moloney leukemia virus (MoLV) is presented and correlates with SAH hydrolase inhibition. Antiviral activity (IC50 against MoLV) ranged from 0.05 to 10 micrograms/mL.
 ...
PMID:4',5'-unsaturated 5'-halogenated nucleosides. Mechanism-based and competitive inhibitors of S-adenosyl-L-homocysteine hydrolase. 199 89

New reactions of methyl 2,2-difluoro glycosides are described that were utilized for synthesis of some novel nucleoside derivatives. Thus, treatment of methyl 2-deoxy-2,2-difluoro-3,4-O-isopropylidene-alpha (beta)-D-erythro-pyranoside (2) with anhydrous HCl resulted in selective displacement of one fluorine atom with chlorine to give a 2-deoxy-2-chloro-2-fluoro glycoside 3. Reaction of 3 with silylated uracil in the presence of SnCl4 provided a 2-deoxy-2-fluoro-2-uracil-substituted glycoside 4. 2-Fluoro-2-deoxy glycosides substituted with other pyrimidines at C-2 were prepared similarly by the reaction of acylated 2,2-difluoro or 2-fluoro-2-bromo derivatives (5 and 6, respectively) with silylated pyrimidines. The resulting 2'-fluorinated isonucleosides were evaluated for their antitumor and antiviral activities. Compounds 7a,b, 8a,b, and 10a,b demonstrated 50% tumor cell growth inhibition in vitro (IC50) at 10(-4)-10(-5) M. At similar concentrations no antiviral activity was observed in vitro. Therapeutic activity was obtained with 7a,b and 8a,b in DBA/2 mice with L1210 leukemia. Administration of 7a,b at 500 mg/kg, ip daily, for 5 consecutive days, resulted in a 55% increase in life span (% ILS) while administration of 8a,b in the same manner at 200 mg/kg caused a 29% ILS. Treatment with 7a,b to mice with drug-resistant L1210 sublines (5-FU and araC) resulted in 22 and 57% increases in life span, respectively. Lewis lung carcinoma and M5076 sarcoma in mice also responded to the administration of 7a,b with reductions in tumor growth for both tumors and significant increases in life span in mice with Lewis lung carcinoma. Although the mechanism of action of 7a,b is not known, it has been found to be a relatively fast-acting, cell-cycle nonspecific cytotoxic agent that decreases [3H]deoxyuridine incorporation, blocks L1210 cells at the G2 phase of the cell cycle, and is not reversed by exogenous thymidine. These 2'-fluorinated isonucleosides have demonstrated biological activity and may have potential as antitumor drugs.
 ...
PMID:2'-Fluorinated isonucleosides. 1. Synthesis and biological activity of some methyl 2'-deoxy-2'-fluoro-2'-pyrimidinyl-D-arabinopyranosides. 270 26

A selected number of 1,3-diaminobenzo[f]quinazolines and 1,3-diamino-5,6-dihydrobenzo[f]quinazolines, which may be viewed as tricyclic analogues of the lipid-soluble antifolates pyrimethamine (PM), metoprine (DDMP), and etoprine (DDEP), were tested as inhibitors of purified dihydrofolate reductase (DHFR) from WI-L2 lymphoblasts, and as inhibitors of the growth of Streptococcus faecium ATCC 8043 and L1210 murine leukemia cells in culture. In addition, these tricyclic compounds were tested for antimalarial activity against Plasmodium berghei in mice, and for the ability to inhibit the growth of Pneumocystis carinii trophozoites in WI-38 human lung fibroblast cultures in the presence of leucovorin (LV). The most potent analogues were those with chlorine substitution in the ring distal to the 2,4-diaminopyrimidine moiety. Fully aromatic compounds tended to be more active than those in which the 5,6-bond was reduced, suggesting that planarity favors binding to the DHFR active site and may be favorable for cellular uptake. Several of the 2,4-diaminopyrimidine analogues showed greater potency than PM, DDMP or DDEP, and were more nearly comparable to the bicyclic 2,4-diaminopyrimidine antifolates trimetrexate (TMQ) or piritrexim (BW301U), which are known to be selectively toxic to P. carinii in the presence of LV. Two of the tricyclic compounds, 1,3-diamino-8-chlorobenzo[f]quinazoline and 1,3-diamino-9-chlorobenzo[f]quinazoline, proved to have activity similar to TMQ and BW301U in this system.
 ...
PMID:Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit Pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin. 278 20

Structures of three antioxidant isoflavonoids isolated from the cultured broth of Streptomyces sp. OH-1049 were shown to be 4',7,8-trihydroxyisoflavone (1), 3',4',7-trihydroxyisoflavone (2) and 8-chloro-3',4',5,7-tetrahydroxyisoflavone (3), respectively. Among them, 3 is a novel isoflavonoid possessing a chlorine atom in the molecule. Compound 1 was synthesized and its antitumor activities were tested against IMC carcinoma, S180, P388 leukemia and P388/ADM leukemia in vivo. As a result, 1 showed 139% increase in life span (ILS) against S180 bearing mice whereas it showed slight or no ILS against IMC carcinoma, P388 leukemia and P388/ADM leukemia bearing mice.
 ...
PMID:Structural study of isoflavonoids possessing antioxidant activity isolated from the fermentation broth of Streptomyces sp. 279 89

A series of derivatives of 5,6-diphenylpyridazin-3-one (DPP) was examined for interactions with calf brain tubulin following the demonstration that many members of the class caused significant mitotic effects in intact animals, while others had activity against murine P388 leukemia. In L1210 cells several DPP derivatives caused a rise in the mitotic index which correlated well with the cytotoxicity of the drugs. Active DPP derivatives markedly stimulated tubulin-dependent guanosine triphosphate hydrolysis and inhibited tubulin polymerization or induced tubulin oligomer formation, depending on specific reaction conditions. These new agents, however, did not interfere with the binding to tubulin of radiolabeled colchicine, vinblastine, maytansine, or guanosine triphosphate. They thus appear to bind at a previously undescribed site on the tubulin molecule. Some DPP derivatives have significant herbicidal activity, causing mitotic disruption and a rise in the mitotic index in seedling root tissues. Although the DPP derivatives most toxic to plant tissues differ from those most active in inhibiting calf brain tubulin polymerization, virtually all active compounds bear a nitrile substituent at position 4 of the pyridazinone ring. Most active derivatives also bear substituents of varying structure at position 2 of this ring, but no clear structure-function pattern is apparent at this position. The phenyl rings in the most active herbicidal DPP derivatives either are unsubstituted or bear fluorine atoms. Derivatives with chlorine substituents have no detectable herbicidal activity. In contrast, interactions with calf brain tubulin are substantially enhanced if the phenyl rings bear chlorine substituents.
 ...
PMID:Derivatives of 5,6-diphenylpyridazin-3-one: synthetic antimitotic agents which interact with plant and mammalian tubulin at a new drug-binding site. 394 71

A patient with prolymphocytic leukemia is described. The peripheral blood and bone-marrow cells contained nuclear pockets, bridges, and appendices, as well as cytoplasmic inclusions that were not membrane bound or connected with the endoplasmic reticulum. X-ray microanalysis of the cells showed them to contain large amounts of phosphorus, sulfur, chlorine, and calcium, as well as a smaller amount of sodium and magnesium in comparison with control lymphocytes. When compared with lymphocytes of a patient with chronic lymphocytic leukemia (CLL), the patient's cells showed higher amounts of magnesium, sulfur, and chlorine, while the sodium content was decreased. The usefulness of electron microscopy and X-ray microanalysis in the diagnosis of this type of leukemia is discussed.
 ...
PMID:Cytoplasmic inclusions and X-ray microprobe analysis in a case of prolymphocytic leukemia. 633 Jan 23


1 2 3 4 5 Next >>