Abstract:
:A series of 96 diarylamidine (and diarylimidazoline) derivatives were evaluated for their inhibitory effects on the growth and DNA synthesis of murine leukemia L1210 cells. The amidino- and imidazolino-substituted aryl moieties of the compounds consisted of phenyl, indole, indene, benzofuran, benzo[b]thiophene or benzimidazole. Several of these compounds were found to inhibit L1210 cell proliferation with an ID50 (50% inhibitory dose) of 1 microgram/ml or lower. Structure-function analysis revealed that the antitumor cell activity of the diarylamidines depended on the planarity of the molecule, the presence of amidino- (or, preferably, imidazolino-) groups on both aryl moieties, the nature of the bridge connecting the two aryl moieties (preferably no bridge at all, phenoxy or ethene) and, finally, the nature of the aryl moieties (preferably, benzofuran or benzo[b]thiophene). Hence, compound 20 (6-(2-imidazolin-2-yl)-2-[4-(2-imidazolin-2-yl)phenyl] benzo[b]thiophene) emerged as the most potent inhibitor of L1210 cell growth (ID50: 0.21 micrograms/ml). Its inhibitory potency was similar to that of the well-known trypanocidal drug ethidium bromide (compound 98). For all diarylamidine derivatives taken together, some correlation (r = 0.612) was noted between the log ID50 for L1210 cell proliferation and the log ID50 for L1210 cell DNA synthesis (as monitored by [methyl-3H]dThd incorporation). These findings suggest that the inhibitory effects of the diarylamidines on L1210 cell proliferation may at least partially reside in an inhibition of DNA synthesis. Compound 41 (2,2'-vinylenedi-1-benzofuran-5-carboxamidine), that exhibited a potent antitumor activity in vitro (ID50: 1.5 micrograms/ml), was further evaluated for its antitumor efficacy in vivo and found to increase the median survival time of L1210 cell-inoculated BDF1 mice up to 204%, if administered at a dose of 200 mg/kg.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Balzarini J,de Clercq E,Dann Odoi
10.1007/BF00172069subject
Has Abstractpub_date
1983-01-01 00:00:00pages
103-15issue
2eissn
0167-6997issn
1573-0646journal_volume
1pub_type
杂志文章abstract::Antiproliferative factor (APF) is a potent frizzled protein 8-related sialoglycopeptide inhibitor of bladder epithelial cell proliferation that mediates its activity by binding to cytoskeletal associated protein 4 in the cell membrane. Synthetic asialylated APF (as-APF) (Galβ1-3GalNAcα-O-TVPAAVVVA) was previously show...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9746-x
更新日期:2012-10-01 00:00:00
abstract::Imidazolium-trans-dimethylsulfoxideimidazoletetrachlororuthenate (NAMI-A) is a ruthenium compound effective on solid tumor metastases. In this study, we evaluated the effects of different routes of administration of NAMI-A on the distribution to primary tumor, lungs and kidneys in BD2F1 hybrids with Lewis lung carcino...
journal_title:Investigational new drugs
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doi:10.1023/a:1022916310694
更新日期:2003-02-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00232346
更新日期:1984-01-01 00:00:00
abstract::Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricul...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-0605-x
更新日期:2018-10-01 00:00:00
abstract:BACKGROUND:Based on reports of the efficacy of docetaxel (T) in STS, we undertook a phase I/II trial to determine the response rate (RR), dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of addition of T to doxorubicin (A) and ifosfamide (I) in advanced STS. METHODS:Patients with advanced, recurrent, or ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-006-9035-2
更新日期:2006-11-01 00:00:00
abstract::Virotherapy is an emerging strategy for the treatment of cancer that utilizes both replication-competent and genetically modified viruses to selectively kill tumor cells. We have previously shown that Coxsackievirus A21 (CVA21), a common-cold producing enterovirus, is an effective oncolytic agent against human melanom...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9614-0
更新日期:2012-04-01 00:00:00
abstract::Nafazatrom, a synthetic pyrazolinone derivative, has been shown to have substantial antitumor activity in vitro and antitumor and antimetastatic activity in experimental animal systems. The drug has produced no substantial toxicity in preclinical studies and during limited human trials. A phase I clinical trial with t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00179592
更新日期:1986-01-01 00:00:00
abstract::Mitonafide is the lead compound of a new series of antitumor drugs, the 3-Nitronaphthalimides, which have shown antineoplastic activity in vitro as well as in vivo. This phase I Mitonafide study in non-small cell lung cancer using a 120-hour continuous infusion (120 h. C.I.) schedule of administration was designed to ...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00877242
更新日期:1992-08-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9370-1
更新日期:2011-04-01 00:00:00
abstract::Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positi...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00928-z
更新日期:2020-12-01 00:00:00
abstract::Myricetin is a naturally omnipresent benzo-α-pyrone flavonoids derivative; has potent anticancer activity. Receptor tyrosine kinases family provides the decisive role in cancer initiation and progression. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer, ow...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0240-8
更新日期:2015-06-01 00:00:00
abstract::Background High-risk neuroblastoma has poor outcomes with high rates of relapse despite aggressive treatment, and novel therapies are needed to improve these outcomes. Ponatinib is a multi-tyrosine kinase inhibitor that targets many pathways implicated in neuroblastoma pathogenesis. We hypothesized that ponatinib woul...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-016-0387-y
更新日期:2016-12-01 00:00:00
abstract::Flavone acetic acid (FAA) was incubated for 1 to 48 hr with 3 established human colon cancer cell lines endowed with distinct degrees of phenotypic properties. All 3 lines responded to FAA in almost identical fashion; when incubated with the drug for only 1 hr, an initial decrease in survival was observed for concentr...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00173501
更新日期:1986-01-01 00:00:00
abstract::3-Deazaguanine (Dezaguanine), a purine antimetabolite, was evaluated in a phase I trial in 42 patients with advanced solid tumors. Dezaguanine was given as a weekly intravenous infusion for three consecutive weeks of a four-week cycle. The dose ranged from 30 to 2000 mg/m2; no consistent dose-limiting hematologic or g...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00198593
更新日期:1990-11-01 00:00:00
abstract::Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dos...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-016-0410-3
更新日期:2017-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-0642-5
更新日期:2019-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9359-9
更新日期:2011-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1007/s10637-010-9591-3
更新日期:2010-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
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更新日期:1996-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0556-7
更新日期:2018-08-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1006260217400
更新日期:1999-01-01 00:00:00
abstract::Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, ...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1016066529642
更新日期:1998-01-01 00:00:00
abstract::Mitoxantrone (Novantrone) and prednimustine (Sterecyt) are both active as single agents in the treatment of unfavorable non-Hodgkin lymphoma (UNHL). The efficacy and toxicity of the combination of these agents (NOSTE) was evaluated in 28 patients with advanced histopathologically proven UNHL who were not eligible for ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00195368
更新日期:1988-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00179430
更新日期:1985-01-01 00:00:00
abstract:BACKGROUND:Lactoferrin is an iron-binding glycoprotein first identified in breast milk as a protein product of mammary epithelial cells. Its immunomodulatory functions include activation of NK and lymphokine-activated killer cells and enhancement of PMN and macrophage cytotoxicity. Studies in animal models have shown p...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-005-3690-6
更新日期:2006-05-01 00:00:00
abstract::SJG-136 is a synthetic pyrrolobenzodiazepine (PBD) dimer in which two DNA-alkylating subunits are linked through an inert propanedioxy tether. Biophysical and biochemical studies of SJG-136 have shown a remarkable affinity for DNA and potent cytotoxicity in vitro. On this basis, together with its unique sequence selec...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/B:DRUG.0000026249.97007.60
更新日期:2004-08-01 00:00:00
abstract:PURPOSE:This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. PATIENTS AND METHODS:Patients with advanced solid tumors refractory to all standard t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9841-7
更新日期:2013-06-01 00:00:00
abstract::Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma wh...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1005989519350
更新日期:1997-01-01 00:00:00
abstract::LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of re...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9640-6
更新日期:2012-06-01 00:00:00
abstract::A series of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-dione derivatives 6 (a-d) and 7 (a-g) were synthesized with different substituted aromatic sulfonyl chlorides (R-SO(2)-Cl) and alkyl halides (R-X) and were characterized by (1)H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evalu...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9130-7
更新日期:2008-10-01 00:00:00