Synthesis of Cyclic Diamino-Substituted Metal Carbene Complexes

Of several lichen metabolites isolated from Parmelia nepalensis and Parmelia tinctorum, the didepsides atranorin (4) and diffractaic acid (5), as well as (+)-protolichesterinic acid (7), inhibited LTB4 biosynthesis in polymorphonuclear leukocytes. Ethyl hematommate (3) and (+)-usnic acid (1) were only weak inhibitors, while methyl β-orcinolcarboxylate (2) and gyrophoric acid (6) were inactive at concentrations up to 60 μM. Redox properties of the compounds were evaluated in terms of inhibition of nonenzymatic lipid peroxidation in model membranes, reactivity against the stable free radical 2,2-diphenyl-1-picrylhydrazyl, and deoxyribose degradation as a measure of hydroxyl-radical generation. The results revealed that lichen metabolites neither acted as antioxidants against the peroxidation process in model membranes nor did they scavenge or produce free radicals, suggesting that the inhibitory effects on LTB4 biosynthesis was due to specific enzyme interaction rather than a nonspecific redox mechanism.

Lichen Metabolites. 1. Inhibitory Action Against Leukotriene B4 Biosynthesis by a Non-Redox Mechanism

A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2- yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1 -/- mice, and at a dose of 50 mg/kg given by ip injection at a qd o- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls. © 2011 American Chemical Society.

Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).

The metabolism of 2-chloro-4-ethylamino-6-isopropylamino-s-triazine (atrazine) in the resistant species, corn (Zea mays L.) and sorghum (Sorghum vulgare Pers.) was not the same. In corn, atrazine was metabolized via both the 2-hydroxylation and N-dealkylation pathways while sorghum metabolized atrazine via the N-dealkylation pathway. Atrazine metabolism in corn yielded the metabolites, 2-hydroxy-4-ethylamino-6-isopropylamino-s-triazine (hydroxyatrazine), 2-hydroxy-4-amino-6-isopropylamino-s-triazine (hydroxycompound I), and 2-hydroxy-4-amino-6-ethylamino-s-triazine (hydroxycompound II). None of these hydroxylated derivatives appeared as metabolites of atrazine in sorghum.Hydroxycompounds I and II were formed in 2 ways in corn: (1) by benzoxazinone-catalyzed hydrolysis of 2-chloro-4-amino-6-isopropylamino-s-triazine (compound I) and 2-chloro-4-amino-6-ethylamino-s-triazine (compound II) that were formed by N-dealkylation of atrazine and (2) by N-dealkylation of hydroxyatrazine, the major atrazine metabolite in corn. The interaction of the 2-hydroxylation and N-dealkylation pathways in corn results in the formation of the 3 hydroxylated non-phytotoxic derivatives of atrazine.

Atrazine Metabolism in Resistant Corn and Sorghum

We have synthesized and evaluated a series of hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A, and alpha-methylene-gamma-butyrolactones with methyl, phenyl, and 4-substituted phenyl groups at the lactone C(gamma) position, denoted 5-17, for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that in general, and especially for 11, 12, and 17, the cytotoxicity of the hybrids was much greater than that of the alpha-methylene-gamma-butyrolactone units 24a-g alone. Using the human leukemia cell line HL-60, we have tested the effects of a selected series of compounds on programmed cell death (apoptosis). The results clearly indicate that 11, 12, and 17, but not 9, are able to induce apoptosis as demonstrated from (i) identification of nuclear changes associated with apoptosis using fluorescence microscopy and (ii) by DNA laddering on agarose gel electrophoresis. Compound 12 was the most potent, especially after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a critical role in chromatin architecture and DNA metabolism.

Design, synthesis, and biological evaluation of hybrid molecules containing alpha-methylene-gamma-butyrolactones and polypyrrole minor groove binders.

Substituted Chlorodiamino-s-triazines1

N-beta-bromoethylaniline hydrobromide.

Alkoxy-s-triazines. III

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Substituted Chlorodiamino-s-triazines1

N-beta-bromoethylaniline hydrobromide.

Alkoxy-s-triazines. III