- Structural studies on bioactive compounds. 32. Oxidation of tyrphostin protein tyrosine kinase inhibitors with hypervalent iodine reagents
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Hydroxylated styrenes (tyrphostins) undergo oxidation by hypervalent iodine oxidants such as [(diacetoxy)iodo]benzene (DAIB) to give a range of products depending on the structure of the phenolic substrate, the solvent, the oxidant stoichiometry, and the purification strategy. Conditions have been developed to modify the phenolic component of the tyrphostin without affecting the appended substituted-vinyl moiety. Novel products include: unstable 2-acyloxy-2-methoxy-4-(substituted-vinyl)cyclohexadienones and their rearrangement products 2-acyloxy-4-hydroxy-3-methoxy-1-(substituted- vinyl)benzenes; phenyliodoniophenolates and their rearrangement products iodophenoxytyrphostins; and 3,3'-dialkoxy-2,2'-dihydroxy-5,5'-di(substituted- vinyl)biphenyls. None of these oxidation products displayed enhanced activity in vitro in the NCI 60-cell line panel or in a panel of human breast cancer cell lines, compared to their tyrphostin precursors. The inhibitory activity of three representative tyrphostins (3e,n, 28) was not modulated by aerobic/anaerobic conditions in MCF-7 and MDA 468 cells and was independent of EGFR status in clones of ZR75B cells transfected with this receptor. Basal growth of MCF-7 cells was unaffected by co-administration of the growth factors EGF, TGF-α, IGF-I, and IGF-II, and the new agents did not inhibit EGFR and c-erbB2 autophosphorylation in cell lysates from MDA 468 or SkBr3 cells, respectively, suggesting that receptor tyrosine kinases are not targets for these compounds. Growth stimulation by the tyrphostin 3n in the ER+ breast cell lines MCF-7, T47D, and ZR75-1 was abolished by 1 μM tamoxifen, suggesting that this compound has estrogen agonist activity.
- Wells, Geoffrey,Seaton, Angela,Steven, Malcolm F. G.
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p. 1550 - 1562
(2007/10/03)
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- Cosmetic composition
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A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamine derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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- Cosmetic composition containing DOPA derivatives
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A composition for topical application to human hair or skin contains a chemical analogue of dihydroxyphenyl alanine (DOPA). This chemical analogue can be absorbed by skin or by a hair follicle and metabolised in-vivo, thus leading to the formation of melanin in skin or to the growth of melanin-pigmented hair. Consequently the composition can give controlled skin darkening to mimic sun-induced tanning or can bring about the growth of dar hair in place of the grey or white hair.
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- Cosmestic composition
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A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamic acid derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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- Polyhydroxylated phenylacrylic acid derivatives as new anti-tumor agents
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Preliminary evidence indicates that antitumor agents containing the o-dihydroxybenzene moiety exhibit enhanced antitumor activity toward malignant cells of high oxidative potential, such as melanoma cells. Based on this consideration, 11 hydroxybenzene acrylic acid derivatives of differing redox potential were prepared as potential substrates for the melanoma specific enzyme tyrosinase, that might exhibit general antitumor activity and enhanced cytotoxicity toward melanoma cells. Five of these compounds [α-cyano-β-(4-hydroxyphenyl)-, α-cyano-β-(3,4-dihydroxyphenyl)-, and α-cyano-β-(3,4,5-trihydroxyphenyl)acrylic acid (THPPA), and 3,4-dihydroxy- and 3,4,5-trihydroxybenzalcyanoacetamide] were found to be substrates for tyrosinase with k(m) values from 0.08 to 4.13 mM and V(max) values from 0.18 to 3.02. These data indicate that as the number of hydroxy groups increases, the rate of oxidation increases, and that cyanoamides were faster reacting than corresponding cyanoacids, with dicyanides the least reactive. In contrast, cyanoamides were less effective as substrates than cyanoacids. In vitro studies showed all but two compounds were active against L1210 (IC50 range 21-980 μM), SK-MEL-28 (IC50 range 54-950 μM), and SK-MEL-30-3 (IC50 range 54-190 μM). Only THPPA was active in vivo against L1210 and B-16 melanoma.
- Hussoin,FitzGerald,Wick
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p. 416 - 418
(2007/10/02)
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- Tyrphostins I: Synthesis and Biological Activity of Protein Tyrosine Kinase Inhibitors
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A novel class of low molecular weight proteine kinase inhibitors is described.These compounds consitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain.These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor.The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 102-103 higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases.These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors.The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth.These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases.We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.
- Gazit, Aviv,Yaish, Pnina,Gilon, Chaim,Levitzki, Alexander
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p. 2344 - 2352
(2007/10/02)
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