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)

In view of the marked antitumor activity of 3-deazauridine, the synthesis of 4-(beta-D-ribofuranosyl)-1,3-dihydroxybenzene (1,3-dideazauridine) and its dibenzyl derivative was carried out. 4-Bromo-1,3-dihydroxybenzene was converted to its dibenzyl derivative, which, upon reaction with n-butyllithium followed by treatment with anhydrous cadmium chloride, gave bis(1,3-dibenzyloxyphenyl-4)cadmium. Condensation of this intermediate with 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride in refluxing toluene, and subsequent removal of the protecting benzoyl groups, afforded 4-(beta-D-ribofuranosyl)-1,3-dibenzyloxybenzene which, upon catalytic hydrogenation over Pd/C, furnished the desired 4-(beta-D-ribofuranosyl)-1,3-dihydroxybenzene. The beta configuration at the anomeric center was established by NMR and hydrogen bonding studies. 4-(Beta-D-ribofuranosyl)-1,3-dibenzyloxybenzene inhibited the growth of leukemia L1210 cells by 50% at 7 x 10(-6) M, and that of mammary carcinoma TA3 cells at 5 x 10(-5) M. Dideazauridine itself was less active, inhibiting the leukemia L1210 but not the TA3 cells at 1 x 10(-4) M, but the compound was significantly active against herpes simplex (type I) virus in vitro.
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PMID:Synthesis and biological activity of 4-beta-Iribofuranosyl-1,3-dihydroxybenzene ("1,3-dideazauridine"). 16 82

2-Deaminoactinomycin D has been synthesized and characterized. It binds to DNA by intercalation according to NMR, CD, thermal denaturation, and unwinding studies on the drug-DNA complex. Loss of the 2-amino group does not seriously affect binding parameters relative to actinomycin D; affinity for calf thymus DNA may even be increased, according to deltaTm measurements. The unwinding of circular DNA caused by this compound is at least as large as that effected by actinomycin D and ethidium bromide. Nevertheless, 2-deaminoactinomycin D is less effective than actinomycin D in inhibiting nucleic acid syntheses in L1210 cell culture and in in vivo antitumor activity against P388 leukemia.
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PMID:2-Deaminoactinomycin D, synthesis and interaction with deoxyribonucleic acid. 33 Aug 57

5,6-Dihydro-8(7H)-quinolinone was synthesized and converted into thiosemicarbazones which could be considered to be semirigid analogues of the 2-formylpyridine thiosemicarbazone class of antitumor agents. The Z and E isomers were separated and identified by 1H NMR and UV. Although the compounds showed essentially no inhibitory activity against the enzyme alkaline phosphatase, several of these agents had demonstrable anticancer activity in mice bearing the P388 leukemia. The E-configuration analogues in general were slightly more active than their corresponding Z isomers.
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PMID:Synthesis of 5,6-dihydro-8(7H)-quinolinone thiosemicarbazones as potential antitumor agents. 33 14

While structure-activity relationships for vinblastine (VLB), vincristine, deacetyl-VLB, and deacetyl-VLB amide (vindesine, VDS) in several tumor and leukemia models have been reported previously, the present study explores these relationships for a series of N-substituted vindesine analogues. These compounds were prepared from the reaction of deacetyl-VLB acid azide with the appropriate amines and were characterized by mass spectral analysis, 1H and 13C NMR spectra, electrometric titration, and infrared spectra. N-Alkylvindesines have reduced activity compared to that of VDS against the Gardner lymphosarcoma (GLS). N-beta-Hydroxyethyl-VDS surpasses vindesine in its activity against the Ridgway osteogenic sarcoma and the GLS, whereas against the B16 melanoma it is less active than VDS. N-beta-(4-Hydroxyphenethyl)-VDS, envisaged as a substrate for the enzyme tryosinase, was shown to be more active than VDS against the B16 melanoma but has only marginal activity against the GLS. In terms of collective antitumor activity against the model systems used, vindesine emerges as the congener with optimum qualities. Bis(N-ethylidenevindesine) disulfide, the first example of a bridged bisvindesine and comparable to VDS in its antitumor profile, shows evidence of activity against a P388/VCR leukemia strain known to be resistant to maytansine as well as to vincristine.
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PMID:Structure-activity relationships of dimeric Catharanthus alkaloids. 2. Experimental antitumor activities of N-substituted deacetylvinblastine amide (vindesine) sulfates. 43 Apr 77

The proton spin lattice relaxation time (T1) of serum and leucocytes of cancer patients and normal volunteers was measured using pulsed NMR techniques. There was no statistically significant difference in the serum T1 values of cancer patients relative to normal. An increase in T1 relative to normal values was detected in the white blood cells of patients with active leukaemia. In these patients T1 fell to normal levels after the initiation of treatment. The variation of leucocyte T1 with the course of the disease for five patients having leukaemia is presented.
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PMID:Proton NMR relaxation times in the peripheral blood of cancer patients. 56 69

A new nitroxyl labeled tetracycline is synthesized. Proton NMR experiments of tetracycline, spin-labeled tetracycline, and the diamagnetic reduced form in DMSO-d6 are reported. The signals observed in the NMR spectra are all assigned. The NMR data revealed that the spin label is attached to the C-2 amide group on ring A of tetracycline. The spin-labeled tetracycline is also tested in vitro for antitumor activity and is found to be active against leukemia P338/ADR cell line and in melanoma LOX cell line.
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PMID:Spectroscopic and biological studies of spin-labeled tetracycline. 131 98

We have previously reported that the antineoplastic agent, procarbazine, in aqueous solutions was chemically oxidized to its azoxy metabolites (methylazoxy and benzylazoxy). To determine if there was additional metabolism of the most active metabolite, methylazoxyprocarbazine, it was incubated in the presence and absence of CCRF-CEM human leukemia cells. Incubations were extracted, and potential metabolites were detected by HPLC with UV detection and by combined HPLC and thermospray mass spectrometric analysis. The major metabolite identified by HPLC with UV detection of the extracts was N-isopropyl-p-formylbenzamide; this was identified by comparison of its retention time with that of a synthesized standard. This identification was further corroborated by HPLC/thermospray mass spectrometry (LC/MS). Analysis of the extracts by LC/MS also showed the presence of a closely eluting peak that had a protonated molecular ion at m/z 207. This new metabolite was identified as N-isopropyl-(benzene-1,4-bis-carboxamide) by 1H NMR and gas chromatography/ion trap mass spectrometry. This metabolite is postulated to arise from breakage of the N-N bond in the hydrazine portion of the molecule. Reconstructed ion (m/z 236) current profiles from the analysis of the cell extracts indicated that there was only a trace amount of methylazoxyprocarbazine left after a 72-hr incubation. Interestingly, a peak with the same molecular weight as the parent compound (methylazoxyprocarbazine) was observed in the cellular incubations and also in extracts of control incubations in which methylazoxyprocarbazine was incubated in medium without cells. This unknown was silylated and identified as a hydroxyazo compound by an ion trap mass spectrometer operated under both single and multiple-stage mass analysis. Formation of this decomposition product appears to involve a novel intramolecular rearrangement of methylazoxyprocarbazine in solution. This pathway may be responsible for the formation of the ultimate cytotoxic species by chemical decomposition of procarbazine.
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PMID:Isolation, purification, and characterization of two new chemical decomposition products of methylazoxyprocarbazine. 135 66

A series of dimers of the monofunctional platinum species [Pt(dien)Cl]+, linked by a variety of flexible (polymethylene) and more rigid chains, was prepared and evaluated for DNA interactions and cytotoxic activity. The polymethylene-linked dimers were prepared by acylation of N(1),N(3)-bistrityldiethylenetriamine with alpha, omega-dicarboxylic acid chlorides, followed by reduction with diborane. Platination of these ligands was achieved with K2PtI4 prepared in situ, followed by anion exchange. Solutions of the bis(Pt(dien)Cl)2+ complexes were stable, and shown to be pure by 195Pt NMR, but solid products could not be isolated. All of the bis(Pt(dien)Cl)2+ complexes unwound closed circular supercoiled DNA more efficiently than the monomer, and were more efficient than the difunctional platinum complex cisplatin at cross-linking linearized plasmid DNA, as measured on non-denaturing agarose gels. None of the bis(Pt(dien)Cl)2+ complexes were as cytotoxic as cisplatin in both the wild-type and platinum-resistant P388 murine leukaemia cell lines. The more rigid analogues were equitoxic in both sensitive and cisplatin-resistant cells, but none showed in vitro activity against the P388 tumour.
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PMID:Synthesis, DNA binding interactions and biological activity of bis platinum (II) complexes of N,N,N',N'-tetrakis(2-aminoethyl)diamines. 138 30

Thalidomide is in clinical use for the treatment of graft-versus-host disease in leukemia patients after bone marrow transplant. Low levels of the drug in plasma after oral administration have made an intravenous thalidomide formulation desirable. Thalidomide, however, is sparingly soluble in aqueous solution (50 micrograms/mL) and unstable. Complexation with hydroxypropyl-beta-cyclodextrin has significantly improved the aqueous solubility and stability of thalidomide. Results obtained with HPLC and 1H NMR spectrometry have demonstrated that the solubility is increased to 1.7 mg/mL and the half-life of a diluted solution is extended from 2.1 to 4.1 h. Hence, an intravenous thalidomide-hydroxypropyl- beta-cyclodextrin solution has the potential to significantly improve current therapy for graft-versus-host disease by providing sustained high levels of drug in the plasma.
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PMID:Improvements in solubility and stability of thalidomide upon complexation with hydroxypropyl-beta-cyclodextrin. 140 4

A series of highly lipophilic platinum(II) complexes of the type cis-[(RNH2)2PtX2] have been synthesized, where R = ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopentyl, or neopentyl and X = either long-chain carboxylate, such as decanoate (C10), laurate (C12), myristate (C14), heptadecanoate (C17), stearate (C18), nonadecanoate (C19), or 2,2,3,3-tetramethylcyclopropylcarboxylate, or branched-chain carboxylate, such as neopentanoate, neohexanoate, neoheptanoate, neononanoate, or neodecanoate. These complexes have been characterized by elemental analysis, IR, and 13C and 195Pt NMR spectroscopic techniques. The platinum complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for antitumor activity. The entrapment efficiency of liposomal platinum (L-Pt) complexes ranged from 60 to 100%. The percentage of T/C obtained after a single i.p. injection of the optimal dose of L-Pt complexes tested against L1210 leukemia ranged from 90 to 125%. These L-Pt preparations did not show significant antitumor activity in mice.
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PMID:Synthesis and biological studies of new lipid-soluble cisplatin analogues entrapped in liposomes. 143 76


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