ABSTRACT
Tobramycin is an aminoglycoside antibiotic that loses a significant amount of activity in the presence of Zosyn at pH 6. As part of our investigation into ways to improve the compatibility of tobramycin with Zosyn (which contains piperacillin and tazobactam in an 8:1 ratio buffered at pH 6 by sodium citrate) by lowering the pH, we identified the reaction product of tobramycin and piperacillin at pH 6.0 and the order of the pK(a) values of tobramycin. The structure of the main reaction product of tobramycin and piperacillin at pH 6.0 was determined by 2D NMR to be the product of 3â³-NH(2) reacting with the ß-lactam of piperacillin. The order of the pK(a) values of the nitrogens of tobramycin was determined by (1)H and (15)N NMR titrations to be 6'-NH(2)>2'-NH(2)>1-NH(2)≈3â³-NH(2)>3-NH(2). At pH 4.0, the reaction between tobramycin and Zosyn was almost negligible for a period of up to 2 h. The pH can be lowered by adding an acid such as HCl or citric acid to Zosyn to make a pH 4.0 buffer.
ABSTRACT
Homotemsirolimuses A, B, and C (2a, 2b, 2c) were found to be minor components of a temsirolimus preparation made from rapamycin. These three temsirolimus analogues are derived from the corresponding rapamycin analogues, homorapamycins A, B, and C (1a, 1b, 1c) produced by the strain Streptomyces hygroscopicus. The structures of homotemsirolimuses A, B, and C were determined by spectroscopic methods. These compounds were tested for mTOR kinase inhibition and in two proliferation assays using LNCap prostate and MDA468 breast cancer cells. The results suggested that the mTOR inhibition and antiproliferation potencies for 2a, 2b, and 2c are comparable to those of rapamycin (1) and temsirolimus (2).
Subject(s)
Antineoplastic Agents/isolation & purification , Sirolimus/analogs & derivatives , Streptomyces/chemistry , TOR Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Female , Humans , Male , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Sirolimus/chemistry , Sirolimus/isolation & purification , Sirolimus/pharmacology , Tacrolimus Binding Proteins/metabolismABSTRACT
The union of HCV-796, a potent selective HCV NS5B polymerase inhibitor, and Ribavirin, a molecule with activities against a wide spectrum of viruses, resulted in a class of new anti-HCV agents with a sequential triple inhibitory mechanism.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Drug Design , Hepacivirus/physiology , Virus Replication/drug effectsABSTRACT
Phosphoinositide 3-kinase (PI3K) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. Wortmannin and its analogues are potent PI3K inhibitors whose therapeutic use has been impeded by inherent defects such as instability and toxicity. Pegylation of wortmannin and 17-hydroxywortmannin gives rise to conjugates with improved properties, including a higher therapeutic index. Pegylated 17-hydroxywortmannin (8, PWT-458) has been selected for further development.
Subject(s)
Androstadienes/chemical synthesis , Antineoplastic Agents/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors , Polyethylene Glycols/chemistry , Androstadienes/chemistry , Androstadienes/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Humans , Mice , Mice, Nude , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/pharmacology , Structure-Activity Relationship , Wortmannin , Xenograft Model Antitumor AssaysABSTRACT
Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.