PubMed · 5142867
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I Guhlke, J Schmidt. 1971. [A comparative study on various antiphlogistics].. https://pubmed.ncbi.nlm.nih.gov/5142867/
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The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts.
Bis(dichlorophosphino)aniline, PhN(PCl(2))(2), reacts with stoichiometric amounts of 2,2'-thiobis(4,6-di-tert-butylphenol) to afford a 10-membered heterocycle, PhN(PCl)(2)[(-OC(6)H(2)((t)Bu)(2))(mu-S)(((t))Bu)(2)C(6)H(2)O-)] (1), in high yield. The structure of the heterocycle has been determined by a single-crystal X-ray analysis. The 10-membered heterocycle 1 reacts with SbF(3) to afford the corresponding fluoro derivative 2 in good yield. The compounds 1 and 2 act as tridentate ligands with molybdenum carbonyl derivatives, forming complexes of the type [Mo(CO)(3)[eta(3)-PhN(PX)(2)[(-OC(6)H(2)((t)Bu)(2))(mu-S)(((t)Bu)(2)C(6)H(2)O-)]-kappa P,kappa P,kappa S]] (3 X = Cl, 4 X = F). A crystal structure of the fluoro derivative 4 showed the facial tricarbonyl complex comprising a relatively strain-free tetracyclic structure with molybdenum in an octahedral environment; the two phosphorus and the sulfur centers were the donor atoms. Compound 2 readily reacts with Ru(II), Pd(II), and Pt(II) derivatives to form chelate complexes, demonstrating the eta(2) mode of coordination.
Methylenedi-p-phenyl diisocyanate (MDI) is widely used in the production of polyurethane products. Diisocyanates are reactive compounds, MDI can react under physiological conditions with various functional groups found on biological molecules resulting in conjugate formation or undergo non-enzymatic hydrolysis to form 4,4'-methylenedianiline (MDA). We have previously reported that addition of MDI directly to Chinese hamster lung fibroblasts (V79) cultures did not induce micronuclei (MN), but MDA, and the glutathione and cysteine conjugates of MDI (BisGS-MDI and BisCYS-MDI), induced a concentration-dependent increase in the frequency of MN. The conventional MN assay does not discriminate between MN produced by acentric chromosome fragments from those arising due to whole lagging chromosomes that were not incorporated into daughter nuclei at the time of cell division. The mechanism of MN induction from these potential MDI metabolites/reaction products was explored in the present study using immunofluorescent staining of kinetochore in MN of cytokinesis-blocked V79 cells. This assay discerns the presence of centromere within the MN to distinguish the MN containing centric chromosomes from those containing acentric fragments. Eighty five percent of MDA-induced MN were negative with respect to anti-kinetochore antibody binding (KC(-)). This is consistent with an interaction between MDA and DNA resulting in chromosome breakage. However, BisGS-MDI and BisCYS-MDI induced a higher percentage of MN that were positively stained by the anti-kinetochore antibody (KC(+)). These results suggest that the mechanism of MN formation induced by BisGS-MDI and BisCYS-MDI is mediated through disruption and/or by affecting the function of the mitotic spindle. This mechanism is distinctly different from the mechanism of MN induction by MDA.