Phase I trial of chloroguinoxaline sulfonamide,with correlation of its pharmacokinetics and pharmacodynamics

To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m². The dose-limiting toxicity was hypoglycemia, first recognized at the 3,700-mg/m² dose. When dose-limiting hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma glucose and insulin concentrations being done in 26 patients. grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m² Concomitant administration of 5% gyciosion being done in 26 patients. Grade 1–3 hypoglycemia close monitoring of plasma glucose and insulin concentrations being done in 26 patients. Grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m². Concomitant administration of 5% glucose did not ameliorate the hypoglycemia associated with CQS doses of >1,000 mg/m². The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of hypoglycemia in 12 patients in whom these data were obtained. Cardiac tachyarrhythmias occured in 7 patients who received CQS at doses of 1,000 mg/m², and tachyarrhythmia was associated with hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of 1,000 mg/m². These toxicities included fever, rash, lightheadedness, leukopenia, thrombocytopenia, alopecia, diarrhea, nausea, and vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged <5%. CQS not bound to plasma protein (free CQS) comprised 1%–17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [glucose], i.e., (predose [glucose]-nadir [glucose]/predose [glucose])×100, correlated with both free and total peak plasma [CQS]. The relationship was described by the Hill equation:Effect=(Emax) (peak) ^H/(peak ₅₀)^H+(peak)^H, where the maximal effect (Emax) equals the maximal possible percentage of decrease in plasma [glucose] equals 100%,peak ₅₀ is the peak total [CQS] at whichE is half-maximal (326 mg/l), andH is the Hill constant, a measure of the sigmoidicity of the relationship (1.06). The relationship fit the data precisely with a mean absolute error (MAE) of 10.42 and was unbiased with a mean error (ME) of –0.06. The recommended phase II dose of CQS is 1,000 mg/m². Because the magnitude of hypoglycemia after CQS administration is related to peak plasma [CQS], repetitive CQS doses of 1,000 mg/m² would probably be tolerated better than single large doses of equivalent intensity.Abbreviations CQS Chloroquinoxaline sulfonamide - AUC area under the plasma concentration x time curve - CLTB total body clearance - MAE mean absolute error - ME mean error - DNA deoxyribonucleic acid - BCNU carmustine [N, N-bis(2-chloroethyl)-N-nitrosourea] - ECOG Eastern Cooperative Oncology Group - WBC white blood cell count - PLT platelet count - ALT alanine aminotransferase - AST aspartate aminotransferase - PT prothrombin time - PTT partial thromboplastin time - EKG electrocardiogram - D5W 5% dextrose in water - HPLC high-performance liquid chromatography - BEE basal energy expenditure This work was supported in part by contract N-01-CM-07303 awarded by the National Cancer Institute, Department of Health and Human Services. One of the authors (B.A.C.) is the recipient of American Cancer Society Clinical Oncology Career Development Award 90-127     

磺胺类黄酮衍生物20S蛋白酶体抑制剂的设计、合成与活性评价

本文通过计算机辅助设计,设计并合成了一系列磺胺类黄酮衍生物作为非共价20S蛋白酶体抑制剂,并对其生物活性进行了测试。与先导化合物相比（β5亚基的IC50值为14.0μM）,化合物仅表现出局部的改善,但仍可作为一类潜在的20S蛋白酶体抑制剂。     

pH-Induced solubility transition of sulfonamide-based polymers

As an approach to designing new pH-sensitive polymers for bio-related application, we have modified selected sulfonamides, with various pK_a, to polymerizable monomers. The pK_a of the monomers, homopolymers, and copolymers with N,N-dimethylacrylamide were examined, and pH-induced phase transition behavior, particularly in solubility, was investigated. The pK_a of sulfonamide monomers and polymers at 25 °C was slightly higher than those of corresponding sulfonamides but the enthalpy of the ionization was influenced due to interfering resonance structures that are present in the mother compounds. The solubility transition of each homopolymer in aqueous solutions occurred at a degree of ionization of 85–90%. For the copolymers, the solubility transition observed by light transmittance completed in a narrow pH range (0.2–0.3 pH units) and this transition pH shifted to a higher pH region with the increasing sulfonamide unit in the copolymer, though the pK_a was not considerably changed. This polymer precipitation occurs because of the relative balance of overall hydrophilicity/hydrophobicity along the polymer chain. Because the unionized form of sulfonamide units is considered to be hydrophobic, the copolymer with higher content of sulfonamide unit requires a higher degree of ionization for solubilization and thus solubility transition occurred at higher pH.     

Anticancer and radio-sensitizing evaluation of some new thiazolopyrane and thiazolopyranopyrimidine derivatives bearing a sulfonamide moiety

Recently, it has been reported that compounds bearing a sulfonamide moiety posses many types of biological activities, including anticancer activity. There are a variety of mechanisms for their anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of some new thiazolo[4,5-b]pyrane, thiazolo[4,5-b]pyrano[2,3-d]pyrimidine derivatives bearing a sulfonamide moiety. The design of the structures of these compounds complies with the general pharmacophoric requirements for CA inhibiting anticancer drugs. The newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to doxorubicin as a reference drug. Compounds 5, 6, 10 and 12 (IC₅₀ values 39.4 μM, 41.6 μM, 35.72 μM and 34.64 μM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC₅₀ = 71.8 μM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.     

Phase I study of E7010

E7010 is a novel sulfonamide which was discovered using slow-growing colon 38 carcinoma cells as a screening model. E7010 exhibits a broad spectrum of antitumor activity against human tumor xenografts. The mechanism of action is by arresting the progression of cells in M phase of the cell cycle by inhibiting tubulin polymerization. The objective of this phase I study was to determine the maximum allowable dose (MAD), toxicity, and pharmacokinetics of single or 5-day repeated doses of E7010. In the single-dose study, E7010 was administered orally to 16 patients at doses ranging from 80 to 480 mg/m². The dose-limiting toxicity was peripheral neuropathy at a dose of 480 mg/m². Hematological and gastrointestinal toxicities were mild. In the 5-day repeated-dose study, 41 patients were given E7010 at doses ranging from 30 to 240 mg/m² per day. The dose-limiting toxicities were peripheral neuropathy and intestinal paralysis. Gastrointestinal toxicity was dose-dependent but not severe. Hematological toxicity was not dose-dependent. Pharmacokinetic analysis in the single-dose study showed a rapid increase in the plasma levels of the drug after administration, followed by disappearance with a t_1/2 of 4.4–16.6 h. The variation in area under the plasma concentration-time curve (AUC) between the patients was small and increased in a dose-dependent manner. Total drug recovery in urine 72 h after administration was 77.8 ± 11.4%, indicating that E7010 has favorable absorption and elimination profiles. The changes in the plasma levels of E7010 on day 5 in the 5-day repeated-dose study were almost the same as those on day 1, indicating that the drug did not accumulate. In the single-dose study, spinal cord metastasis exhibited a 74% reduction in a patient with uterine sarcoma and a minor response (MR) was observed in a pulmonary adenocarcinoma patient. In the 5-day repeated-dose study decreases in the tumor markers carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) were observed in a patient with stomach cancer and in a patient with recurrent uterine cervical carcinoma, respectively. The recommended phase II doses are 320 mg/m² for a single-dose study and 200 mg/m² per day for a 5-day repeated-dose study. Since the activity of E7010 is time-dependent, i.e. a certain concentration of E7010 is required for more than 12 h to suppress the growth of P388 leukemia cells, it is recommended that subsequent phase I/II studies be conducted using a divided dose schedule in order to maintain the blood level of E7010. Received: 12 February 1997 / Accepted: 6 November 1997     

Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model

Background and purpose

Carbonic anhydrase (CA) IX is suggested to be an endogenous marker of hypoxia. Fluorescent sulfonamides with a high affinity for CA IX (CAI) have been developed and shown to bind to cells only when CA IX protein was expressed and while cells were hypoxic. The aim of this study was to investigate the in vivo CAI binding properties in a xenograft tumour model using fluorescent imaging.

Materials and methods

NMRI-nu mice subcutaneously transplanted with HT-29 colorectal tumours were treated with 7% oxygen or with nicotinamide and carbogen and were compared with control animals. CAI accumulation was monitored by non-invasive fluorescent imaging.

Results

Specific CAI accumulation could be observed in delineated tumour areas as compared with a non-sulfonamide analogue (P < 0.01). Administration of nicotinamide and carbogen, decreasing acute and chronic hypoxia, respectively, prevented CAI accumulation (P < 0.05). When treated with 7% oxygen breathing, a 3-fold higher CAI accumulation (P < 0.01) was observed. Furthermore, the bound CAI fraction was rapidly reduced upon tumour reoxygenation (P < 0.01).

Conclusions

Our in vivo imaging results confirm previous in vitro data demonstrating that CAI binding and retention require exposure to hypoxia. Fluorescent labelled sulfonamides provide a powerful tool to visualize hypoxia response. An important step is made towards clinical applicability, indicating the potential of patient selection for CA IX-directed therapies.     

Synthesis and in vitro anticancer evaluation of some novel hexahydroquinoline derivatives having a benzenesulfonamide moiety

Inhibition of carbonic anhydrase isozymes has been found to have a role in the treatment of cancer. Several sulfonamide compounds bearing an aromatic or a heteroaromatic ring were found to posses potent carbonic anhydrase inhibitory activity and so can be used in the treatment of several types of cancer. In this paper, we present the synthesis of some novel quinoline 7-13, 21-26, 28 and pyrimidoquinoline 14-18, 20, 27 derivatives having a sulfonamide moiety. All the newly synthesized compounds were evaluated for their in vitro anticancer activity. Several compounds showed interesting cytotoxic activities when compared with the used reference drug. In addition, docking of the synthesized compounds into carbonic anhydrase isozyme II (CA II) active site was performed in order to give a suggestion about the proposed mechanism of action.     

土壤中11种磺胺类兽用抗生素的超高效液相色谱-串联质谱测定法

目的 建立土壤中11种磺胺类兽用抗生素的超高效液相色谱-串联质谱测定法.方法 样品用0.1 mol/L EDTA提取液(乙腈:柠檬酸=1∶1)提取,SAX-HLB串联固相萃取柱净化,以C18超高效色谱柱分离,采用串联质谱电喷雾离子源(ESI),在多反应监测正离子模式下测定,外标法定量.结果 该方法在6 min内完成了11种抗生素的快速分离检测.加标水平为2.5、10、50μg/kg时,11种抗生素的回收率为69.6％～98.5％,RSD为5.9％～15.2％;在2～200 μg/L的浓度范围内呈良好线性关系(r＞0.9988),检出限为0.23 ～ 1.64 μg/kg.结论 与传统液相色谱法相比,该方法分析时间短,适用于土壤样品中多种磺胺类抗生素的检测.     

环维黄杨星D磺酰化衍生物的合成及耐缺氧活性的研究

目的寻找更多具有治疗心脑血管疾病的潜在药物。方法通过磺酰化反应将不同取代的磺酰氯中间体连接到环维黄杨星D上,合成得到目标产物,并对其进行耐缺氧活性的研究。结果和结论共合成了7个环维黄杨星D磺酰化衍生物,其结构经IR、MS1、HNMR和高分辨质谱(HRMS)确证,且化合物2 a~2g均具有良好的药理活性,其中化合物2 e、2g作用最强,超过现有临床药物黄杨宁片。     

Die blutzuckersenkende Wirkung von Sulfafurazol und Sulfamethoxazol an der Ratte

Zusammenfassung Die beiden Sulfonamide Sulfafurazol und Sulfamethoxazol senken die Blutglucosekonzentration von Ratten im Hunger. Diese Wirkung tritt dosisabhängig auf und erreicht bei 450 mg Sulfafurazol/kg bzw. 200 mg Sulfamethoxazol/kg ein Maximum. Da beide Sulfonamide methylierte Isoxazolringe enthalten, wurde untersucht, ob dieser Effekt mit der blutzuckersenkenden Wirkung des 3,5-Dimethylisoxazol vergleichbar ist, das vor allem bekannt geworden ist, weil es die Konzentration der unveresterten Fettsäuren im Blut erniedrigt. Es zeigte sich jedoch, daß die Wirkung beider Sulfonamide eher der hypoglykämischen Reaktion auf das Sulfonylharnstoffderivat Tolbutamid entspricht. Die Konzentration der unveresterten Fettsäuren im Plasma wurde durch Tolbutamid und Sulfafurazol geringfügig, durch Sulfamethoxazol nicht erniedrigt. Bei schwer alloxandiabetischen Ratten vermochten Sulfafurazol und Sulfamethoxazol ebensowenig wie Tolbutamid die erhöhte Konzentration der Glucose und der Fettsäuren im Blut zu senken. An eviscerierten Ratten, deren Pankreas bei dem Eingriff entfernt wurde, waren beide Sulfonamide ebenso wie Tolbutamid ohne Wirkung auf die Blutzuckerwerte. Dagegen war der blutzuckersenkende Effekt ebenso wie der des Tolbutamids bei hepatektomierten Ratten mit erhaltener endokriner Pankreasfunktion nachzuweisen. Obwohl in der Isoxazolgruppe des Sulfamethoxazols ein Stoff gefunden wurde, der in niedrigen Dosen die Konzentration der unveresterten Fettsäuren im Plasma senkt, schließen diese Ergebnisse aus, daß die geprüften Sulfonamide entweder selbst oder über aus ihnen gebildete Metabolite die Glucosekonzentration im Blut in gleicher Weise erniedrigen, wie die Lipolysehemmstoffe vom Typ des 3,5-Dimethylisoxazols. Ihre Wirkung an der Ratte entspricht vielmehr derjenigen des Tolbutamids. Da Ratten besonders empfindlich auf Sulfafurazol und Sulfamethoxazol reagieren und selbst hier hohe Dosen erforderlich waren, um einen Effekt auf die Blutglucosekonzentration nachzuweisen, erscheint es wenig wahrscheinlich, daß diese Verbindungen bei der üblichen Dosierung am Menschen hypoglykämische Zwischenfälle auslösen können.Herrn Professor Dr. L. Lendle in Verehrung zum 70. Geburtstag gewidmet.