Potential antitumor agents. 21. Structure determination and antitumor activity of imidazo[2,1-b]thiazole guanylhydrazones.
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Biomedical subjects
Publications and source records attributed to M Rambaldi.
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We cloned two homeobox genes, Emx1 and Emx2, related to empty spiracles, a gene expressed in very anterior body regions during early Drosophila embryogenesis, and studied their expression in mouse embryos. Emx1 expression is detectable from day 9.5 of gestation whereas Emx2 appears to be already expressed in 8.5 day embryos. Both genes are expressed in the presumptive cerebral cortex and olfactory bulbs. Emx1 is expressed exclusively there, whereas Emx2 is also expressed in some neuroectodermal areas in embryonic head including olfactory placodes in earlier stages and olfactory epithelia later in development.
The synthesis of phenothiazine and anthraquinone derivatives, bearing at least one fragment present in lotifazole, is reported. Some of the new compounds showed antitumor activity in vitro (P388 leukemia cells) and in vivo (Ehrlich ascites tumor cells in mice).
A number of imidazo[2,1-b]thiazoles bearing a 2,6-dichlorophenyl group as hydrazone or as amide were prepared and tested in rats as antihypertensive agents. Only compounds bearing a chlorine at position 6 were active.
The synthesis of three series of new imidazo [2,1-b] thiazoles (nitriles 1-7, amides 8-14 and p-sulfamidophenylhydrazones 15-24) is reported. Among the compounds tested, only 12 showed a borderline diuretic activity. Compounds 15-24, possible prodrugs of sulfanilamide, were devoid of antibacterial activity.
We isolated and mapped the human homeobox gene EVX1. This gene encodes a protein of 407 amino acid residues containing a homeodomain closely related to the Drosophila even-skipped (eve) segmentation gene of the pair-rule class. EVX1 belongs to a small family of vertebrate eve-related homeobox genes including human EVX1 and EVX2 genes, their murine homologs, Evx 1 and Evx 2, and the frog Xhox-3 gene. We previously reported that EVX2 is localized at the 5' end of the HOX4 locus on chromosome 2. We show here that EVX1 is localized at the 5' end of the HOX1 locus on chromosome 7, 48 kb upstream from the most 5' of the eleven HOX1 genes, namely HOX1J. Both EVX genes are transcribed in an opposite orientation as compared to that of adjacent HOX genes. Human HOX1 and HOX4 complex loci appear to be both closely linked to a homeobox gene of the EVX family.
We describe the case of a 42 year old woman with abdominal pain, ascites, and splenomegaly after having taken dihydroergotamine continuously for three months due to frequent hemicranic episodes. The celiac-mesenteric angiography demonstrated diffuse thrombosis of splenic, superior mesenteric and portal veins. No surgical intervention was possible. We believe that it is possible that dihydroerogotamine, a hydrogenated derivative of ergotamine, inasmuch as it is capable of causing peripheral vasoconstriction, intimal lesions, arterial and venous thrombi, was also the cause of our patient's portal thrombosis. We therefore suggest the minimum effective amount of the drug be utilized to achieve the relief of cephalalgia.
The synthesis of two series of 1-(N-methylanilinoethyl)indoles is reported. The first arises from the N-alkylation of indole-3-acetic acid or its methylester, while the second was prepared by means of the Witting reaction on the appropriate aldehyde. The compounds were tested in mice (hot plate test and phenyl-p-benzoquinone induced writhing test) for their analgesic activity. None of the compounds was significantly active in the hot plate test. However, N-methylanilinoethyl 1-(N-methylanilinoethyl)-3-indolylacetate (7) was the most active one in the phenyl-p-benzoquinone induced writhing test, which indicates that 7 has a peripheral analgesic effect.
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1-Phenylalkylindole-3-carboxylic acids 1-4, indole-1-acetic acids/esters 5-10 and the hydrazones 11-15 were prepared and submitted to the rat paw edema test using carrageenin. In the first two groups of compounds, the 2-chloro indoles were more active than the corresponding indole derivatives. In the third group the activity seemed to be determined largely by the substituent at the 1-position.
We studied the expression of 33 human homeobox genes belonging to four complex HOX loci in embryonal carcinoma NT2/D1 cells. These cells can be induced to differentiate by culturing them in media containing retinoic acid. Northern blot analysis reveals that no expression of these genes was detectable in NT2/D1 stem cells, whereas 22 HOX genes are well expressed in NT2/D1 cells treated with 10 microM retinoic acid for 14 days. The 11 HOX genes the expression of which remained undetectable in NT2/D1 cells after this treatment are located at the 5' end of their loci: four in HOX1, five in HOX3 and two in HOX4. The boundary between induced and silent genes roughly corresponds to the HOX genes constituting the homology group 5, related to the Abdominal-B homeotic gene of Drosophila. All nine identified HOX2 genes are well expressed in fully induced NT2/D1 cells and none of them maps 5' genes of this homology group. We conclude that HOX genes are differentially activated by retinoic acid in these cells according to their physical location within the four chromosomal loci.
New indole derivatives and their intermediates were tested as cytotoxic agents on a culture of P388 leukemia cells. The aldehyde 2a was more active than the thiosemicarbazones 3a, b and the nitrosourea 14. The chloroacetyl derivatives 10, 11 were the most potent cytotoxic agents.
Slides prestained with acridine orange (AOS) were used for direct examination of microorganisms in clinical specimens. The method is simpler than a commonly used acridine orange stain (AO) and has the advantage of being a supravital stain. Results indicate that the AOS method is sensitive, and allows rapid detection of microorganisms, even in the specimens containing few microorganisms, e.g. cerebrospinal fluid. Moreover AOS may be the choice method for detection of Trichomonas vaginalis.
The synthesis of 5-methoxy- (IX) and 5-hydroxy- (X) 2-chloro-3-formyl-6-methylindole is reported: three hydrazonic derivatives were prepared from each compound. Preliminary results on the activity of the six derivatives against P388 leukemia in mice are reported.
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Some thiosemicarbazones of 1-acyl-2-chloro-3-formylindoles were synthesized and investigated for antiviral activity against vaccinia virus, HID stock and parainfluenza virus type 3 HA-I/CR-8 stock. Evidence of antiviral activity was found only against vaccinia virus, and was particular significant with the m-substituted 1-benzoyl-2-chloro-3-formylindoles. The first results of 2-substitution of chlorine by bromine in the indole skeleton, are reported.