Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a-o and 6a-g) and their corresponding free amines 5a-m and 7a-g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d-g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI50 values over the tested cancer cells, and low cytotoxic effects (GI50 > 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI50 and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC50 = 2.25 µM), FGFR4 (IC50 = 6.71 µM) and Tie2 (IC50 = 6.84 µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.

Three novel lower rim hexamide derivatives 5(6), 7(6), and 9(6) of p-hydroxycalix[6]arene and four octamides 5(8), 7(8)-9(8) derived from the corresponding p-hydroxycalix[8]arene were synthesized, and their potential as extractants in radioactive waste treatment was evaluated, in comparison with upper rim analogues 12(6) and 12(8) and other existing selective neutral ionophores currently used in radioactive waste treatment. Extraction of alkali and alkaline earth metal picrates from water to dichloromethane, and of the corresponding nitrates from acidic water solution simulating radioactive waste, to 2-nitrophenyl hexyl ether (NPHE), showed that the lower rim amides extract divalent cations much better than monovalent ones. The upper rim hexa-12(6) and octamide 12(8) are very inefficient ligands, hardly extracting any cation. In all cases, p-alkoxy octamides are more efficient and selective extractants than the corresponding hexamides. In the case of simulated waste solutions, the distribution coefficients for strontium removal by octamides (6.5 < D(Sr) < 30) are much higher than the corresponding value (D(Sr)) found for dicyclohexyl-18-crown-6 (DC18C6), and the same applies for the strontium/sodium selectivity, which is 6500 < D(Sr)/D(Na) < 30 000 for octamides and 47 for DC18C6. ESI-MS, UV-vis, and X-ray crystal structure studies give consistent results and indicate the formation of 2:1 (cation/ligand) strontium complexes for all octamides tested. Stability constants were determined in homogeneous methanol solution for alkali metal (log beta(11) < or = 2), calcium (4.3 < or = log beta(11) < or = 6.0; 9.4 < or = log beta(21) < or = 12.0), and strontium (5.6 < or = log beta(11) < or = 12.3) ions using a UV-vis competition method with 1-(2-pyridylazo)-2-naphthol (PAN). They confirm the high efficiency and high divalent/monovalent selectivity found in metal ion extraction experiments for the new octamide ligands. Evidence for a positive cooperative effect between the two metal ion binding sites was obtained in the case of the Ca(2+) complex of octamide 1(8).

Diagnostic evidence or symptoms of gastroparesis develop in about 20% to 30% of patients with long-standing diabetes. Diabetic gastroparesis is likely caused by autonomic neuropathy involving the nerves that regulate gastric motor function. The following are necessary for diagnosis: thorough history taking and physical examination to eliminate factors that might further delay gastric emptying; esophagogastroduodenoscopy or barium contrast studies to exclude structural abnormalities; and a radionuclide gastric emptying study. The three main agents available for therapy in the United States are metoclopramide (Maxolon, Octamide, Reglan), erythromycin, and cisapride (Propulsid). All have been shown to offer benefit in improving gastric emptying and symptoms, although use of metoclopramide is limited by a significant incidence of side effects. Surgical intervention should be avoided if possible.

In some patients, peptic lesions fail to heal after 2 to 3 months of standard histamine2 (H2) receptor antagonist or sucralfate (Carafate) therapy. Noncompliance with prescribed treatment, cigarette smoking, gastric acid hypersecretory states (including Zollinger-Ellison syndrome), Helicobacter pylori infection, the use of nonsteroidal anti-inflammatory drugs, abdominal radiation therapy, and malignant tumors are all causes of refractory disease. Treatment options include high-dose H2 receptor antagonist therapy or switching to a more potent drug or one with a different mechanism of action. Occasionally, drug combinations (eg, H2 receptor antagonist plus misoprostol [Cytotec] for gastric ulcers or H2 receptor antagonist plus metoclopramide [Octamide, Reglan] for reflux disease) are effective. Triple-drug therapy for H pylori infection with refractory duodenal ulcers may allow healing and dramatically decrease recurrence rates. When surgery is required, vagotomy and antrectomy is probably the procedure of choice in patients with peptic ulcer disease that is refractory to medical management. Nissen fundoplication is effective in patients with reflux esophagitis who have adequate esophageal motility.