We aimed to examine whether individuals with type 2 diabetes (T2D) exhibit suppressed leg vascular conductance and skeletal muscle capillary perfusion in response to a hyperinsulinemic-euglycemic ...clamp and to test whether these two variables are positively correlated. Subsequently, we examined whether T2D-associated skeletal muscle microvascular insulin resistance, as well as overall vascular dysfunction, would be ameliorated by an 8-wk walking intervention (45 min at 60% of heart rate reserve, 5 sessions/week). We report that, relative to healthy subjects, overweight and obese individuals with T2D exhibit depressed insulin-stimulated increases in leg vascular conductance, skeletal muscle capillary perfusion, and Akt phosphorylation. Notably, we found that within individuals with T2D, those with lesser increases in leg vascular conductance in response to insulin exhibited the lowest increases in muscle capillary perfusion, suggesting that limited muscle capillary perfusion may be, in part, linked to the impaired ability of the upstream resistance vessels to dilate in response to insulin. Furthermore, we show that the 8-wk walking intervention, which did not evoke weight loss, was insufficient to ameliorate skeletal muscle microvascular insulin resistance in previously sedentary, overweight/obese subjects with T2D, despite high adherence and tolerance. However, the walking intervention did improve (
< 0.05) popliteal artery flow-mediated dilation (+4.52%) and reduced HbA1c (-0.75%). It is possible that physical activity interventions that are longer in duration, engage large muscle groups with recruitment of the maximum number of muscle fibers, and lead to a robust reduction in metabolic risk factors may be required to overhaul microvascular insulin resistance in T2D.
This report provides evidence that in sedentary subjects with type 2 diabetes diminished insulin-stimulated increases in leg vascular conductance and ensuing blunted capillary perfusion in skeletal muscle are not restorable by increased walking alone. More innovative physical activity interventions that ultimately result in a robust mitigation of metabolic risk factors may be vital for reestablishing skeletal muscle microvascular insulin sensitivity in type 2 diabetes.
A structure−activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell ...growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineoplastic activity, and the benzophenone derivative of combretastatin A-1 was therefore synthesized. The benzophenone, designated hydroxyphenstatin (6a), was synthesized by coupling of a protected bromobenzene and a benzaldehyde to give the benzhydrol with subsequent oxidation to the ketone. Hydroxyphenstatin was converted to the sodium phosphate prodrug (6e) by a dibenzyl phosphite phosphorylation and subsequent benzyl cleavage (6a → 6d → 6e). While hydroxyphenstatin (6a) was a potent inhibitor of tubulin polymerization with activity comparable to that of combretastatin A-1 (3a), the phosphorylated derivative (6e) was inactive.
Continued investigation of cancer-cell growth-inhibitory constituents of the blue marine sponge Cribrochalina sp. has led to discovery of cribrostatins 3 (4a), 4 (5), and 5 (4b) in 10-5 to 10-7 % of ...the wet weight. The structure of cribrostatin 3 (4a) was determined by results of high field (500 MHz) 1H and 13C NMR and HRMS interpretations. The same general approach to the structures of cribrostatins 4 (5) and 5 (4b) was completed by X-ray crystal structure determinations. Cribrostatins 3, 4, and 5 provided significant cancer cell line inhibitory activities. Cribrostatins 1 and 2 and the newly isolated cribrostatins 3−5 displayed antibacterial and/or antifungal activities.
The antineoplastic constituents of Combretum caffrum (Eckl. and Zeyh) Kuntze (Combretaceae family), a species indigenous to South Africa, have been investigated. Subsequently we isolated a series of ...closely related bibenzyls, stilbenes, and phenanthrenes from C. caffrum. Some of the stilbenes proved to be potent antimitotic agents which inhibited both tubulin polymerization and the binding of colchicine to tubulin. Combretastatin A-4 has been shown to be the most potent cancer cell growth inhibitor of the series. Presently this cis-stilbene is the most effective inhibitor of colchicine binding to tubulin and the simplest natural product yet described with such potent antitubulin effects. Combretastatin A-4, A-5, and A-6 were also found to inhibit growth of Neisseria gonorrhoeae. Details of the isolation and syntheses of combretastatins A-4 (2a), A-5 (2c), and A-6 (3a) have been described.
The South African willow tree Combretum caffrum has yielded a number of potent cancer cell growth inhibitors. The present SAR studies of the antineoplastic agent combretastatin A-4 (1c) were focused ...mainly on the olefinic bridge to determine the effects on cancer cell growth and, potentially, to better define the combretastatin A-4 binding site on tubulin. The geometric trans-isomer 3a of combretastatin A-4 was converted to the (1S,2S)- and (1R,2R)-vicinal diols 4c and 4d, respectively, under Sharpless' asymmetric dihydroxylation conditions. Cancer cell line testing showed the (1S,2S)-diol 4c to be more potent than its enantiomer 4d. Diol 4c weakly inhibited tubulin polymerization (IC50 = 22 μM, versus 1.2 μM for combretastatin A-4), while 4d was inactive (IC50 > 40 μM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.
Cribrostatin 6, a dark blue cancer cell growth inhibiting (P388 ED(50) 0.3 microg/mL) constituent of the Republic of Maldives marine sponge Cribrochalina sp., has been assigned structure 3 on the ...basis of a combination of HRMS, high-field (500 MHz, HMBC, and GOESY experiments) (15)N, (1)H, and (13)C NMR, and X-ray crystal structure analyses. Cribrostatin 6 also was found to inhibit the growth of a number of pathogenic bacteria and fungi.
A series of cis- and trans-stilbenes related to combretastatin A-4 (1a), with a variety of substituents at the 3‘-position of the aryl B-ring, were synthesized and evaluated for inhibitory activity ...employing six human cancer cell lines (NCI-H460 lung carcinoma, BXPC-3 pancreas, SK-N-SH neuroblastoma, SW1736 thyroid, DU-145 prostate, and FADU pharynx-squamous sarcoma) as well as the P-388 murine lymphocyte leukemia cell line. Several of the cis-stilbene derivatives were significantly inhibitory against all cell lines used, with potencies comparable to that of the parent 1a. All were potent inhibitors of tubulin polymerization. The corresponding trans-stilbenes had little or no activity as tubulin polymerization inhibitors and were relatively inactive against the seven cancer cell lines. In terms of inhibition of both cancer cell growth and tubulin polymerization, the dimethylamino and bromo cis-stilbenes were the most potent of the new derivatives, the latter having biological activity approaching that of 1a. As part of the present study, the X-ray crystal structure of the 3‘-O-phosphate of combretastatin A-4 (1b) was successfully elucidated. Compound 1b has been termed the “combretastatin A-4 prodrug”, and it is currently undergoing clinical trials for the treatment of human cancer patients.
The Indo-Pacific marine sponge Ircinia ramosa has been found to contain two powerful (GI50 from 0.001 to <0.0001 microg/mL) murine and human cancer cell growth inhibitors. Both were isolated ...(10(-3)-10(-4)% yields) by cancer cell line bioassay-guided techniques and named irciniastatins A (1) and B (2). Structural elucidation by a combination of spectral analyses, primarily high resolution mass and 2D-NMR (principally APT, HMQC, HMBC, and ROESY) spectroscopy, revealed the unusual structures 1 and 2.
A Streptomyces sp. isolated from riverbank soil in Manitoba, Canada, was found to contain two cancer cell growth inhibitories: diazaanthraquinone 1 and 3-(hydroxyacetyl)indole (8). The structures ...were determined by interpretation of data from HRMS, UV, and high-field (400 MHz) NMR experiments. The red-colored diazaanthraquinone 1 and 3-(hydroxyacetyl)indole (8) were found to inhibit (0.1-3 microg/mL) growth of a minipanel of human cancer cell lines and P388 lymphocytic leukemia cells. Diazaanthraquinone 1 was also found to inhibit growth of the bacteria Streptococcus pneumoniae and Neisseria gonorrheae. However, three companion constituents, cyclo-Pro-Leu (5), cyclo-Pro-Phe (6), and cyclo-Pro-Val (7), did not inhibit cancer cell growth.
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