In our ongoing research program aimed at the optimization of microtubule-self-assembly disrupting agents, we have prepared three series of phenylurea analogues (CEU), derived from N-(3-omega-hydroxyalkyl or 4-omega-hydroxyalkyl or 3-omega-hydroxyalkynyl)-phenyl-N'-(2-chloroethyl)ureas. Most compounds exhibit potent growth inhibitory activity on human colon carcinoma HT-29, human skin melanoma M21, and human breast carcinoma MCF-7 tumor cell lines, with a GI50 ranging from 250 nM to 8 microM. Among these new molecules, three CEUs exhibit GI50 in the nanomolar range. They are more potent by approximately an order of magnitude than previously described CEU analogues. As such, they are attractive hit compounds for the development of potent new alkylating antitubulin drugs.
Objective: To identify the decision-making needs of women about the use of natural health products (NHP) at menopause and to develop a decision aid responsive to their needs. Design: A qualitative study using focus groups, key informant interviews and group consultation. Content analysis was guided by the Ottawa Decision Support Framework. Methods: Six focus groups with menopausal women aged 45 to 64 (n 40) and key informant interviews (n 15; physicians, nurses, women's advocacy group, NHP stores owners, pharmacists, policy makers) were conducted in two Canadian cities. Two groups of menopausal women (n 11) were consulted to obtain feedback on the acceptability of the new patient decision aid. Results: The most common difficult decisions identified by women were: whether or not to take NHP; which NHP to choose; and whether or not to take anything for menopausal symptoms. In addition, key informants identified the challenge of choosing between hormone therapy and NHP for menopausal symptoms. The main sources of difficulty in making these decisions were the following: (1) inadequate knowledge and unrealistic expectations associated with NHP; (2) closed mindedness of physicians to discussion about NHP; (3) conflicting opinions of others; (4) inadequate resources to support NHP decision-making (e.g., information, finances, time); and (5) menopausal symptoms interfering with decision-making (e.g., lack of sleep due to hot flashes). To facilitate decision making, participants suggested the need for information about available choices, tighter regulation of NHP by the government, and access to health professionals conversant in NHP and medical options. The patient decision aid was developed according to the International Patient Decision Aid Standards and based on women's identified needs. Women described the aid as easy to understand and useful for considering the decisions about NHP. Conclusions: Middle-age women reported difficulty when facing decisions about the use of NHP. Many sources of difficulty could be addressed in the patient decision aid. Subsequent studies should evaluate the effect of this decision aid on the decision-making process of women.
A series of para-substituted phenoxypropanolamines has been synthesized and tested for beta-adrenoceptor blocking activity. Some derivatives (8, 11, 12, 20, 21) exhibited greater in vitro potency than the reference drugs metoprolol and propranolol. This series, in contrast to propranolol but similar to metoprolol, possesses cardioselectivity. The 3-[p-[(cycloalkylmethoxy)ethyl]phenoxy]-1-substituted-amino-2-prop anol derivatives 8 (cyclopropylmethoxyethyl: betaxolol) and 11 (cyclobutylmethoxyethyl) produced antihypertensive effects in spontaneously hypertensive rats. Betaxolol (Kerlon, 8) was found to exhibit an appropriate preclinical pharmacological and human pharmacokinetic profile (elevated oral bioavailability and prolonged plasma half-life) for the treatment of chronic cardiovascular diseases such as hypertension and angina.
Microtubule disruption provokes cytoskeleton and cell adhesion changes whose importance for apoptosis induction remains unclear. The present study focuses on the functional and the molecular adhesion kinetics that are induced by microtubule disruption-mediated apoptosis. We showed that antimicrotubules induce a biphasic sequence of adhesion response that precedes the onset of apoptosis and focal adhesion kinase hydrolysis. Antimicrotubules first induced an increase of the cellular adhesion paralleled by the raise of focal adhesion sites and actin contractility, which was followed by a sharp decrease of cell adhesion and disorganization of focal adhesion and actin stress fibers. The latter sequence of events ends by cell rounding, detachment from the extracellular matrix, and cell death. Microtubule-disrupting agents induced a sustained paxillin phosphorylation, before the activation of apoptosis, that requires the prior activation of extracellular signal-regulated kinase and p38 but not c-Jun NH 2 -terminal kinase. Interestingly, integrin-linked kinase overexpression rescued the antimicrotubule-mediated loss of cell viability. Altogether, these results propound that antimicrotubule agents induce anoikis through the loss of focal adhesion structure integrity.Focal adhesions (FAs) are specialized complexes of structural and signaling proteins that assemble or disassemble as cell migrate or enter into mitosis. They form, following the integrin-mediated cell attachment to extracellular matrices (ECM), anchoring actin filaments and microtubules (MTs) to the membrane of the cell (Mitra et al., 2005). One of the cornerstone proteins of FA architecture is paxillin (Brown and Turner, 2004). Paxillin connects integrins to the actin cytoskeleton via vinculin and talin (Brown and Turner, 2004) and focal adhesion kinase (FAK), the integrin-linked kinase (ILK) (Nikolopoulos and Turner, 2001). After integrin ligation, FAK undergoes tyrosine autophosphorylation, which triggers interactions with Src-family tyrosine kinases for its maximal activation. The FAK-Src complex further activates several signaling pathways, notably the prosurvival phosphatidylinositol 3-kinase/Akt pathway (Khwaja et al., 1998)
In the course of the development of N-phenyl-N'-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents, we investigated the effect of carbonylated substituting chains of the aromatic ring of CEU on their covalent binding to the colchicine-binding site (C-BS). In this study, we found that CEU, 5e, 5f, 8e, and 8f substituted by either a methyl ester or a methyl ketyl group at the omega-position exhibited a significant antiproliferative activity on HT-29, M21, and MCF-7 tumor cells. SDS-PAGE assays and cell cycle analysis confirmed that 5e, 5f, 8e, and 8f covalently bind to the C-BS and arrest the cell division in G(2)/M phase. Surprisingly, the presence of omega-carboxyl, omega-ethyl esters or omega-amides decreased significantly both the antiproliferative activity and the specificity toward beta-tubulin.
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