Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity

1991 ◽  
Vol 34 (1) ◽  
pp. 98-107 ◽  
Author(s):  
William D. Kingsbury ◽  
Jeffrey C. Boehm ◽  
Dalia R. Jakas ◽  
Kenneth G. Holden ◽  
Sidney M. Hecht ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Topoisomerase I ◽  
Water Soluble ◽  
Camptothecin Analogs

Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase I

1995 ◽  
Vol 38 (3) ◽  
pp. 395-401 ◽  
Author(s):  
Michael J. Luzzio ◽  
Jeffrey M. Besterman ◽  
David L. Emerson ◽  
Michael G. Evans ◽  
Karen Lackey ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Topoisomerase I ◽  
Water Soluble ◽  
Derivatives Of ◽  
Specific Inhibitors

scholarly journals Comparison of In Vitro Activities of Camptothecin and Nitidine Derivatives against Fungal and Cancer Cells

1999 ◽  
Vol 43 (12) ◽  
pp. 2862-2868 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Shih-Fong Chen ◽  
Daniel Von Hoff ◽  
Christine C. Dykstra ◽  
Mansukh C. Wani ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Mammalian Cells ◽  
Topoisomerase I ◽  
Active Form ◽  
Antifungal Drugs ◽  
Water Soluble ◽  
Yeast Cells ◽  
Original Structure ◽  
Camptothecin Analogs

ABSTRACT The activities of a series of camptothecin and nitidine derivatives that might interact with topoisomerase I were compared against yeast and cancer cell lines. Our findings reveal that structural modifications to camptothecin derivatives have profound effects on the topoisomerase I-drug poison complex in cells. Although the water-soluble anticancer agents topotecan and irinotecan are less active than the original structure, camptothecin, other derivatives or analogs with substitutions that increase compound solubility have also increased antifungal activities. In fact, a water-soluble prodrug appears to penetrate into the cell and release its active form; the resulting effect in complex with Cryptococcus neoformanstopoisomerase I is a fungicidal response and also potent antitumor activity. Some of the compounds that are not toxic to wild-type yeast cells are extremely toxic to the yeast cells when the C. neoformans topoisomerase I target is overexpressed. With the known antifungal mechanism of a camptothecin-topoisomerase I complex as a cellular poison, these findings indicate that drug entry may be extremely important for antifungal activity. Nitidine chloride exhibits antifungal activity against yeast cells through a mechanism(s) other than topoisomerase I and appears to be less active than camptothecin analogs against tumor cells. Finally, some camptothecin analogs exhibit synergistic antifungal activity against yeast cells in combination with amphotericin B in vitro. Our results suggest that camptothecin and/or nitidine derivatives can exhibit potent antifungal activity and that the activities of camptothecin derivatives with existing antifungal drugs may be synergistic against pathogenic fungi. These new compounds, which exhibit potent antitumor activities, will likely require further structural changes to find more selective activity against fungal versus mammalian cells to hold promise as a new class of antifungal agents.

ChemInform Abstract: Synthesis of Water-Soluble (Aminoalkyl)camptothecin Analogues: Inhibition of Topoisomerase I and Antitumor Activity.

ChemInform ◽  
2010 ◽  
Vol 22 (22) ◽  
pp. no-no
Author(s):  
W. D. KINGSBURY ◽  
J. C. BOEHM ◽  
D. R. JAKAS ◽  
K. G. HOLDEN ◽  
S. M. HECH ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Topoisomerase I ◽  
Water Soluble ◽  
Camptothecin Analogues

Novel water soluble phosphate prodrugs of taxol® possessing in vivo antitumor activity

1993 ◽  
Vol 3 (8) ◽  
pp. 1761-1766 ◽  
Author(s):  
Yasutsugu Ueda ◽  
Amarendra B. Mikkilineni ◽  
Jay O. Knipe ◽  
William C. Rose ◽  
Anna Maria Casazza ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Water Soluble ◽  
Soluble Phosphate ◽  
In Vivo Antitumor Activity

Synthesis of 14-Azacamptothecin, a Water-Soluble Topoisomerase I Poison

2005 ◽  
Vol 7 (5) ◽  
pp. 835-837 ◽  
Author(s):  
Nicolas J. Rahier ◽  
Kejun Cheng ◽  
Rong Gao ◽  
Brian M. Eisenhauer ◽  
Sidney M. Hecht
Keyword(s):  
Topoisomerase I ◽  
Water Soluble

scholarly journals In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2817-2828 ◽  
Author(s):  
FM Uckun ◽  
CF Stewart ◽  
G Reaman ◽  
LM Chelstrom ◽  
J Jin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Topoisomerase I ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Water Soluble ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
B Lineage

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.

scholarly journals Epigallocatechin Gallate-Gold Nanoparticles Exhibit Superior Antitumor Activity Compared to Conventional Gold Nanoparticles: Potential Synergistic Interactions

Nanomaterials ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 396 ◽  
Author(s):  
Suhash Chavva ◽  
Sachin Deshmukh ◽  
Rajashekhar Kanchanapally ◽  
Nikhil Tyagi ◽  
Jason Coym ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Nuclear Translocation ◽  
Epigallocatechin Gallate ◽  
Drug Carriers ◽  
Water Soluble ◽  
Tetrazolium Salt ◽  
Uptake Studies

Epigallocatechin gallate (EGCG) possesses significant antitumor activity and binds to laminin receptors, overexpressed on cancer cells, with high affinity. Gold nanoparticles (GNPs) serve as excellent drug carriers and protect the conjugated drug from enzymatic metabolization. Citrate-gold nanoparticles (C-GNPs) and EGCG-gold nanoparticles (E-GNPs) were synthesized by reduction methods and characterized with UV-visible spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Cytotoxicity of citrate, EGCG, C-GNPs, and E-GNPs was evaluated by the water-soluble tetrazolium salt (WST-1) assay. Nanoparticle cellular uptake studies were performed by TEM and atomic absorption spectroscopy (AAS). Dialysis method was employed to assess drug release. Cell viability studies showed greater growth inhibition by E-GNPs compared to EGCG or C-GNPs. Cellular uptake studies revealed that, unlike C-GNPs, E-GNPs were taken up more efficiently by cancerous cells than noncancerous cells. We found that E-GNP nanoformulation releases EGCG in a sustained fashion. Furthermore, data showed that E-GNPs induced more apoptosis in cancer cells compared to EGCG and C-GNPs. From the mechanistic standpoint, we observed that E-GNPs inhibited the nuclear translocation and transcriptional activity of nuclear factor-kappaB (NF-κB) with greater potency than EGCG, whereas C-GNPs were only minimally effective. Altogether, our data suggest that E-GNPs can serve as potent tumor-selective chemotoxic agents.

DX-8951f, a Hexacyclic Camptothecin Analog, on a Daily-Times-Five Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies

2000 ◽  
Vol 18 (17) ◽  
pp. 3151-3163 ◽  
Author(s):  
Eric K. Rowinsky ◽  
Thomas R. Johnson ◽  
Charles E. Geyer ◽  
Lisa A. Hammond ◽  
S. Gail Eckhardt ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Level ◽  
Compartment Model ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Water Soluble ◽  
Severe Thrombocytopenia ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Wide Range

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m2/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m2/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m2/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.

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