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Biomedical subjects

M Cushman

Publications and source records attributed to M Cushman.

At least 127 records · Page 7Linked to original sources
PubMed1992

Inhibition of HIV-1 integration protein by aurintricarboxylic acid monomers, monomer analogs, and polymer fractions.

Several aurintricarboxylic acid (ATA) monomers, monomer analogs, and polymer fractions have been tested as inhibitors of HIV-1 integration protein (IN). Both of the ATA monomers and all of the ATA polymer fractions inhibited a selective DNA cleavage reaction catalyzed by IN. The ATA monomer analogs were inactive or had low activity. The activities of the substances as inhibitors of HIV IN correlated in a positive way with their activities as inhibitors of the cytopathic effect of HIV-1 in CEM and HIV-2 in MT4 cells. These results suggest that inhibition of HIV IN may contribute to the antiviral activity of the ATA monomers and monomer analogs in cell culture.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Preparation and anti-HIV activities of aurintricarboxylic acid fractions and analogues: direct correlation of antiviral potency with molecular weight.

Aurintricarboxylic acid (ATA) was fractionated by a combination of dialysis, ultrafiltration, and gel permeation chromatography. The number average and weight average molecular weights of the ATA fractions were determined by the universal calibration method. The sulfonic acid analogue of ATA was prepared and separated in high and low molecular weight fractions. The phosphonic acid analogue of ATA was also synthesized. All of the ATA fractions were tested for prevention of the cytopathic effect of HIV-1 and HIV-2 in MT-4 cell culture as well as against HIV-1 in CEM cell culture. The abilities of the fractions and analogues to inhibit syncytium formation between HIV-1- and HIV-2-infected HUT-78 cells and uninfected MOLT-4 cells were evaluated. In addition, the fractions and analogues were tested for cytotoxicity in mock-infected MT-4 cells, prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor, inhibition of the binding of anti-gp120 monoclonal antibody to gp120, inhibition of attachment of HIV-1 virions to MT-4 cells, and inhibition of HIV-1 reverse transcriptase. In all of these assays except cytotoxicity, there was a correlation of potency with molecular weight. The higher the molecular weight, the higher the activity. Several of the lower molecular weight fractions of ATA, which bound to gp120 but not to CD4, prevented HIV-1 and HIV-2 cytopathicity. A similar profile was observed for the phosphonic acid analogue of ATA and the lower molecular weight fraction of the sulfonic acid analogue. The results on the ATA fractions indicate that the binding of ATA to gp120 in the absence of CD4 binding is sufficient for anti-HIV activity. The active compounds bind more avidly to gp120 than to CD4. The anti-HIV activity of the ATA fractions is due to inhibition of virus binding due to an interference with the gp120-CD4 interaction.

Antiviral Agents↗
PubMed1991

Synthesis and anti-HIV activities of low molecular weight aurintricarboxylic acid fragments and related compounds.

Several compounds corresponding to fragments of the schematic representation of the polymeric structure of aurintricarboxylic acid (ATA) have been prepared and tested for prevention of the cytopathic effect of HIV-1 and HIV-2 in MT-4 cell culture and HIV-1 in CEM cell culture. Both the triphenylcarbinol 3 as well as the triphenylmethane 5 were found to afford protection against the cytopathogenicity of HIV-2 in MT-4 cells and HIV-1 in CEM cells, but they were inactive against HIV-1 in MT-4 cells. Both substances were also found to inhibit syncytium formation when MOLT-4 cells were cocultured with HIV-2-infected HUT-78 cells, but were inactive in this assay against HIV-1-infected cells. When observed, the activity is generally moderate in degree of protection and requires concentrations in the 10(-4) molar range. In contrast to ATA, both of these substances were inactive when tested for prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor and also for inhibition of HIV-1 reverse transcriptase. These substances therefore appear act by a mechanism that is distinct from that of polymeric ATA. Several active and inactive structural analogues of 3 and 5 were also synthesized. The anti-HIV activity in this series seems to depend on the presence of anionic carboxylate groups, since the methyl esters 4, 6, and 12 were uniformly inactive. The diphenylmethanes 8, 14, 18, and 19 also reproducibly inhibited the cytopathic effect of HIV-1 in CEM cell culture.

Antiviral Agents↗
PubMed1991

Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues.

Treatment of o-hydroxyacetophenones 2a-e with excess lithium bis(trimethylsilyl)amide followed by dialkyl carbonates gave alkyl 3-(2-hydroxyaryl)-3-oxopropanoates 3a-e. The latter substances were transformed through the reaction of their magnesium chelates with benzoyl chlorides into a series of 3-(alkoxycarbonyl)-2-arylflavones, which were subsequently elaborated into a variety of flavonoids. These compounds were tested for their abilities to inhibit the in vitro protein-tyrosine kinase activity of p56lck, an enzyme which is thought to play a key role in mediating signal transduction from the CD4 receptor during lymphocyte activation. All of the active compounds had either an amino or a hydroxyl substituent at the 4'-position of the 2-aryl ring. The most active substance prepared in this study is compound 17c, which is approximately 1 order of magnitude more potent than the natural product quercetin (1). Compound 17c was a competitive inhibitor of p56lck with respect to ATP and was highly selective for the inhibition of protein-tyrosine over protein-serine/threonine kinases.

Chemical Phenomena↗
PubMed1991

Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization.

An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a greater than 8a greater than 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a greater than 8a greater than 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.

Antineoplastic Agents↗
PubMed1991

Functional scoring of multi-trauma patients: who ends up where?

To help map the continuum from injury to return to full function, the Functional Independence Measure (FIM) was used in an acute care setting to identify and track disability, to focus rehabilitative efforts during the acute phase of care, and to help demonstrate what is truly important in getting patients back to full functional status. A total of 109 patients were assessed over a 13-month period. FIM scores were based on a patient's ability to routinely perform certain tasks in 18 areas of function and ranged from 1 to 7. The change in FIM scores from admission to discharge was used to determine those patients to be discharged home and those patients to be discharged to a rehabilitation facility. We conclude that the FIM is a very useful tool that produced a very good measure of a patient's total function, tracked progress or lack of it through acute hospitalization, and correctly categorized and quantitated dysfunction (both cognitive and physical) as discharge planning was being done.

Activities of Daily Living↗
PubMed1990

Synthesis of [beta-(4-pyridyl-1-oxide)-L-alanine4]-angiotensin I as a potential suicide substrate for protein-tyrosine kinases.

An asymmetric synthesis of [beta-(4-pyridyl-1-oxide)-L-alanine4]-angiotensin I (1a), which is a potential suicide substrate (mechanism-based inhibitor) for protein-tyrosine kinases, has been performed. Deprotonation of 6 with n-butyllithium in THF gave the anion 7, which was alkylated with 4-(chloromethyl)pyridine-1-oxide to afford intermediate 9 as a crystalline solid. Hydrolysis of 9 afforded a mixture of 11 and 12 in a ratio of 96:4 as estimated by conversion to the diastereomeric dipeptides 13 and 14 followed by HPLC analysis. The 96:4 mixture of 11 and 12 was used in the solid phase synthesis of the target angiotensin analog 1a and its diastereomer 1b, which were separated and tested for inhibitory activity against two thymocyte protein-tyrosine kinases: p40 and p56lck. Neither peptide displayed significant inhibitory activity toward p40 and both served as weak competitive inhibitors of p56lck.

Angiotensin I↗
PubMed1987

Management of vascular trauma.

Despite a nationwide 55 mph speed limit, and amid rising interpersonal violence, vascular injuries exact a great toll in morbidity and mortality. The identification, anatomic diagnosis, and repair of civilian traumatic vascular injuries still present a challenge.The concepts and precepts concerning vascular injury learned during World War II were responsible for the improved rates of limb salvage in the Vietnam War and remain pertinent in present-day civilian practice.The key factors concerning clinical evaluation, laboratory diagnosis, and definitive surgical therapy for major vascular injuries are outlined and elucidated.

Blood Vessel Prosthesis↗
PubMed1985

Synthesis and antitumor activity of structural analogues of the anticancer benzophenanthridine alkaloid fagaronine chloride.

The indenoisoquinoline analogue 4 of fagaronine chloride (2) has been prepared, as well as its positional isomer 20 and the corresponding mesylated derivatives 16 and 19. Compounds 4, 16, and 20 were tested against P388 lymphocytic leukemia and found to possess significant activity. A tricyclic analogue 24 was also synthesized and was devoid of cytotoxicity in the KB cancer cell culture system. The change in the substitution pattern of the A-ring on going from 4 to 20 was tolerated without producing a significant decrease in antitumor activity.

Alkaloids↗
PubMed1984

Synthesis and biological activity of structural analogues of the anticancer benzophenanthridine alkaloid nitidine chloride.

The indenoisoquinoline analogue 9 of nitidine (1) has been prepared and found to possess significant anticancer activity against L1210 lymphoid leukemia, P388 lymphocytic leukemia, and B16 melanocarcinoma. Analogue 14, which lacks the B ring of nitidine (1), has also been synthesized. Compound 14 retains the in vitro toxicity associated with nitidine (1) but is devoid of antileukemic activity. The structural factors that may contribute to the difference in biological activity between the two closely related analogues 9 and 14 are discussed.

Animals↗
PubMed1979

Conformations, DNA binding parameters, and antileukemic activity of certain cytotoxic protoberberine alkaloids.

The tetrahydroprotoberberine alkaloids 5 and 7 possessing a trans-quinolizidine conformation display in vitro KB cytotoxicities in contrast to their corresponding diastereomers 4 and 6 which exist in the cis-quinolizidine conformation and are much less toxic. The DNA-binding parameters of these compounds as well as the protoberberine salts 1, 8, and 9 have been examined by equilibrium dialysis. Only the quaternary salts bind to DNA. The alcohol 5 showed low in vivo activity against leukemia P388 systems, while the quaternary salts 8 and 9 proved to be toxic to the host.

Animals↗