Dianilinophthalimides represent a novel class of inhibitors of the EGF-receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Steady-state kinetic analysis of compound 3, which showed potent inhibitory activity, revealed competitive type kinetics relative to ATP. Despite a highly symmetrical structure of compound 3, X-ray studies revealed an unsymmetrical propeller-shaped conformation of the molecule which differs clearly from that of the constitutionally related staurosporine aglycons. These conformational differences may explain the reversal of the selectivity profile of compound 3 relative to the staurosporine aglycons. In cellular assays compounds 3 and 4 have been shown to inhibit EGF-induced receptor autophosphorylation, c-fos induction and EGF-dependent proliferation of Balb/c MK cells. This inhibition was selective as compounds had no effect on PDGF-induced receptor autophosphorylation and c-fos induction. Furthermore, compound 3 showed potent antitumor activity in vivo at well-tolerated doses.
The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.
Es wird über die Isolierung und Identifizierung der 6 Indolalkaloide Kopsinin (I), 19,20‐Dihydroakuammicin (II), Tubifolin (III), Tubifolidin (IV), Tubotaiwin (V) und Tuboxenin (VII) aus den Blättern von Pleiocarpa pycnantha (K. SCHUM.) STAPF, var. tubicina ( STAPF) PICHON berichtet.
A number of semisynthetic bicyclomycin derivatives have been prepared by modifications at various sites of the molecule. The preparation, characterization and antimicrobial evaluation of the new compounds is described. In contrast to bicyclomycin itself, the new derivatives 48 and 58 are also active against Proteus species. Otherwise, the antibacterial potency of the bicyclomycin molecule was found to be very sensitive to structural changes. The isolation of bicyclomycin'2 from Streptomyces sapporonensis ATCC 21532 was reported in 1972 by the research laboratories of Fujisawa Pharmaceutical Co. Ltd. The structural elucidation 2,''e, antibacterial properties" and mechanism of actions) have been the subjects of further communications from this group*. The antimicrobial spectrum of bicyclomycin, its low toxicity and its novel structure prompted us to initiate a project for the chemical modification of this antibiotic. The present paper describes the preparation, chemical characterization and the microbiological properties of a number of new semisynthetic derivatives obtained in our laboratories. Chemical Modifications A considerable number of esters of the primary hydroxyl group have been described by KAMIYA et a1.2,s' In extension of this work, we have now prepared the carbonates 2, 3 and 4 by reaction of 1 with the corresponding chloroformates. One noteworthy feature in this series was the formation of the cyclic carbonate 4, obtained with 2,2,2-trichloroethyl-chloroformate, and its rearrangement to the isomeric 1',2'-carbonate 5 in methanolic solution at ambient temperature. The carbamate 6 was prepared easily from 1 and ethyl isocyanate. The reaction of bicyclomycin with dihydropyrane/p-toluenesulfonic acid can be conducted to give either the monoether 8 or the diether 12". Acylation of 8 with benzoyl chloride-pyridine, separation of 9 from the dibenzoate 10, and removal of the protecting group led to the C-1'-benzoate ester 11. In a similar way, 6-0-acetyl-bicyclomycin 14 was obtained from the di-THP-ether 12 via the intermediate 13**. These sequences illustrate the application of THP-protected intermediates for selective transformations at C-l' or C-6. With mesyl chloride-pyridine, bicyclomycin 1 was converted to the mesylate 15, which on treatment with triethylamine furnished the epoxide 16 in 70% yield***. Both 15 and 16 are potential intermediates for derivatives carrying a nitrogen-or sulfur functional group at C-3'. Attempts to prepare 3'-amino derivatives by reacting either 15 or 16 with ammonia or isopropylamine failed, and instead the tricyclic compound 17 was formed in low yield together with other compounds of as yet * The absolute configuration has just recently been determined by MAAG et a1 .13> ** Acetylation of unprotected bicyclomycin yields triacetate 72,6). *** 16 is also accessible via 3'-O-tosyl-bicyclomycin7) .
Mc/s untersucht und liess ein bei 6,OQ z zentriertes Quartett und ein bei 2,28 z gelegenes Dublett ( J = 7,9 c/s) erkennen; diese Signale entsprechen den in der analogenEinen Einblick in das Skelett des Pleiocarpins vermittelte die Zinkstaubdestillation des Alkaloids, wobei man in der Fraktion dei starken Basen 3,5-Diathylpyridin (identifiziert als Pikrat) und in der Fraktion der schwachen Basen @-Athylindol (charakterisiert als Pikrat) isolierte. Aus der letzteren Fraktion wurden ferner Mischkristalle von hauptsachlich 3-Methylcarbazol mit 3-bthylcarbazol und Carbazol
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