108 results about "Dihydrofolate reductase deficiency" patented technology

The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.

The invention relates to application of DNA (Deoxyribonucleic Acid)-PKcs in preparation of a medicine for influencing dihydrofolate reductase (DHFR) gene amplification and changing the drug resistance of tumor cells on MTX (Methotrexate) and belongs to biological medicines. The application comprises the following steps: establishing an MTX drug-resistant cell evolution model, selecting low-concentration drug-resistant (HSRs) and high-concentration drug-resistant (DMs) cells as research objects, detecting the gene amplification degree and form in the parent cells and drug-resistant cells, the DNA damage conditions and DNA-PKcs expression conditions, establishing clone which stably interferes the DNA-PKcs in the MTX drug-resistant cells aiming at the core protein DNA-PKcs in the NHEJ path, and detecting the amplification degree and form of DHFR genes in stable interference clone, the cell growth and apoptosis and change of the drug resistance.

Compounds of Formula I and Formula IA are inhibitors of dihydrofolate reductase and are suitable for use in compositions and methods for dihydrofolate reductase inhibition or, more specifically, treatment of a fungal infection, a bacterial infection or a protozoal infection, and, in specific embodiments, treatment of a fungal infection caused by C. albicans or C. glabrata:

wherein R, R₁, R₂, R₃, R₄, A, B, E, V, W, X, Y and Z are as defined herein.

Recombinant lentiviral vectors having a region encoding a functional β-globin gene; and large portions of the β-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of β-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including β-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than un-transformed cells allows selection by treatment of the cells with the corresponding drug.

The present invention relates to a novel gene expression system comprising: a) a first nucleotide sequence encoding a fusion polypeptide of: a1) a destabilizing domain (DD) based on DHFR, and a2) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and b) a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. The invention also relates to use of this gene expression system together with a ligand binding to a destabilizing domain (DD) based on dihydrofolate reductase (DHFR) for treatment of diseases associated with a reduced dopamine level, such as Parkinson's disease.

The invention relates to an acetamides compound and application thereof, and discloses an N-(4-substituted phenyl ethyl) amides compound with a novel structure. An in vitro activity test experiment proves that the compound has the enzyme inhibitory activity on cysteine proteinase (FP-2) and dihydrofolate reductase (DHFR); a malaria-killing experiment result proves that the compound has an inhibition effect on wild and drug-resistant malaria protozoon.

The present invention relates to novel compounds that are inhibitors of wild type and mutant dihydrofolate reductase (DHFR) of Plasmodium falciparum, which are useful for the treatment of malaria. It also relates to processes of making and using such compounds. The antimalarial compounds of the present invention have low toxicity to a host infected with the malarial parasite, and are potent when administered in pharmaceutical compositions.

Antisense oligomers directed to bacterial cell division and cell cycle-encoding nucleic acids are capable of selectively modulating the biological activity thereof, and are useful in treatment and prevention of bacterial infection. The antisense oligomers are substantially uncharged, and contain from 8 to 40 nucleotide subunits, including a targeting nucleic acid sequence at least 10 nucleotides in length which is effective to hybridize to (i) a bacterial tRNA or (ii) a target sequence, containing a translational start codon, within a bacterial nucleic acid which encodes a protein associated with cell division or the cell cycle. Such proteins include zipA, sulA, secA, dicA, dicB, diCc, dicF, ftsA, ftsl,ftsN, ftsK, ftsL, ftsQ, ftsw, ftsZ, murC, murD, murE, murF, murg, minC, minD, minE, mraY, mraW, mraZ, seqA, ddlB, carbamate kinase, D-ala D-ala ligase, topoisomerase, alkyl hydroperoxide reductase, thioredoxin reductase, dihydrofolate reductase, and cell wall enzyme.

The compositions and methods described herein discloses the design, synthesis and testing of compounds that act as inhibitors of DHFR. The basic scaffold of these inhibitors includes a 2,4-diaminopyrimidine ring with a propargyl linker to another substituted aryl, bicyclo or heteroaryl ring. These DHFR inhibitors are potent and selective for many different pathogenic organisms, including the DHFR enzyme from bacteria such as Bacillus anthracis and methicillin-resistant Staphylococcus aureus, fungi such as Candida glabrata, Candida albicans and Cryptococcus neoformans and protozoa such as Cryptosporidium hominis and Toxoplasma gondii. These compounds and other similar compounds are also potent against the mammalian enzyme and may be useful as anti-cancer therapeutics.

Compounds of the formula I: wherein R1, R2, R1' and R2' are independently hydrogen or a group releasing the free amine in vivo, R6 is a substituted phenyl or an optionally substituted, bicyclic or tricyclic aryl ring system or an optionally substituted mono, bi- or tricyclic heteroaryl ring system having utility as DHFR inhibitors with favourable pharmacokinetic properties.

Sol-gel derived monolithic silica columns containing entrapped dihydrofolate reductase were used for frontal affinity chromatography of small molecule mixtures. The output from the column combined with a second stream containing the matrix molecule (HCCA) and was directly deposited onto a conventional MALDI plate that moved relative to the column via a computer controlled x-y stage, creating a semi-permanent record of the FAC run. The use of MALDI MS allowed for a decoupling of the FAC and MS methods allowing significantly higher ionic strength buffers to be used for FAC studies, which allowed for better retention of protein activity over multiple runs.

The invention relates to a Chinese hamster ovary (CHO) cell line capable of showing Rta albumen of Elzatein-Barn (EB) virus stably and efficiently, a creation method and application thereof and a cell base built by the CHO cell line, and belongs to the technical field of biology. Preservation number of the recombination cell line CHO/RTA is CGMCC6955, the CHO cell base expressing the Rta albumen of the EB virus can be used for practical production and formed by the recombination cell line CHO/RTA. The invention further provides a method for creating the CHO cell line. Dihydrofolate reductase defect type Chinese hamster ovary cells (CHO/dhfr-) serve as host cells, and the cell line capable of expressing the Rta albumen of the EB virus stably and efficiently is obtained after screening and amplification of the host cells.

The invention relates to a geographically-specific Plasmodium vivax molecule marker, and its application in strain tracing. The molecule marker includes a Plasmodium vivax circumsporozoite protein center replication region reflecting mosquito infection differences of different media, a height polymorphism microsatellite reflecting mutation, migration and genetic drift, and a drug resistance related gene mutation reflecting the population positivity selection of drug control. Results show that each of a Plasmodium vivax circumsporozoite protein center replication region sequence, dihydrofolate reductase SNP, dihydrobiopterin synthetase SNP, a neutral microsatellite and the like has a geographic specificity, and can be used as a classification index in tracing detection.

Compounds of formula (I) or (II) are dihydrofolate reductase inhibitors, useful for the treatment of, for example, cell proliferative diseases:

wherein A and D are independently —CHR₇— or —NR₇—; E and G are independently ═CR₇— or ═N—; each R₆ independently represents hydrogen or —OR₇; R₇ is hydrogen or C₁-C₆ alkyl; R₁ is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R₂ is the side chain of a natural or non-natural alpha amino acid which does not contain a carboxyl, or carboxyl ester group; Y is a bond, —C(═O)—, —S(═O)₂—, —C(═O)NR₃—, —C(═S)—NR₃, —C(═NH)NR₃ or —S(═O)₂NR₃— wherein R₃ is hydrogen or optionally substituted C₁-C₆ alkyl; L¹ is a divalent radical of formula -(Alk¹)_m(Q)_n(Alk²)_p- wherein m, n and p are independently 0 or 1, and Q, Alk¹ and Alk² are as defined in the claims; X¹ represents a bond; —C(═O); or —S(═O)₂—; —NR₄C(═O)—, —C(═O)NR₄—, —NR₄C(═O)NR₅—, —NR₄S(═O)₂—, or —S(═O)₂NR₄— wherein R₄ and R₅ are independently hydrogen or optionally substituted C₁-C₆ alkyl; and z is 0 or 1.

The invention provides a eukaryotic expression vector capable of selecting high expression clones conveniently and high efficiently. The eukaryotic expression vector is obtained via structure modification by taking pBudCE4.1 carrier as a basic carrier; peptide chain elongation factor gene promoter (P) on the basic carrier, and multiple cloning sites on the downstream of the peptide chain elongation factor gene promoter (P) are replaced by an expression element composed of attenuated SV40 promoter and dihydrofolate reductase gene on the downstream of the attenuated SV40 promoter; multiple cloning sites on the downstream of cytomegalovirus early promoter (P) of the basic carrier are replaced by new multiple cloning sites.

The invention relates to a preparation method and pharmacological application of novel 3-methoxy-4-(N-substituted amino sulfonyl)fenalamide derivatives. The structural general formula of the derivatives is shown in a formula (I), wherein R1 and R2 are defined as the specifications. The compounds can serve as small molecular double inhibitors for Falcipain-2 and dihydrofolate reductase (DHFR), simultaneously blocks hemoglobin hydrolysis under the action of cysteine protease and inhibits the reduction activity of the DHFR, so as to inhibit multiplication of plasmodium. Therefore, the compounds can be expected to be developed into double-target-based novel antimalarial medicines.