Synthesis and Cytotoxicity of 2,4-Disubstituted and 2,3,4-Trisubstituted Brominated Pyrroles in Murine and Human Cultured Tumor Cells

Gupton, John T.; Burham, B. S.; Krumpe, Keith E.; Du, Karen; Sikorski, James A.; Warren, Amy E.; Barnes, Cheryl R.; Hall, Iris H.

doi:10.1002/(sici)1521-4184(200001)333:1<3::aid-ardp3>3.0.co;2-4

Cited by 18 publications

(25 citation statements)

References 23 publications

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“…These compounds represent an emerging class of agents with potential activity against a variety of human tumors with activity expressed at nM or µM concentrations in human tumor cell lines [18,19], but having advantages over natural products in terms of drug design and development. In particular, we have been exploring a series of brominated pyrroles whose structure suggests that they might interfere with tubulin function.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, we have been exploring a series of brominated pyrroles whose structure suggests that they might interfere with tubulin function. One member of this series (JG-03-14, 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester), for which NCI tumor panel activity had been obtained [19], was suggested by COMPARE [16] to have an activity profile similar to colchicine. Cellular studies with JG-03-14 further support the contention that these compounds function as microtubule poisons [18].…”

Section: Resultsmentioning

confidence: 99%

“…In addition, JG-03-14 was found to have the capacity to promote both autophagic and apoptotic cell death, albeit in different cell lines, while retaining activity in tumor cells expressing the multidrug resistant pump P-glycoprotein [18,24]. Because the development of additional synthetic or semi-synthetic pyrrole derivatives in this class is facilitated with their relatively facile syntheses, including modification of the molecule by adding and removing functional groups [19], we have both a rather extensive collection of molecules in-hand (Scheme 1) for building predictive molecular models and the potential for rational design and synthesis of many others.…”

Section: Resultsmentioning

confidence: 99%

“…Results from a number of assays have previously appeared regarding the antiproliferative and cytotoxic activities of the lead compound JG-03-14 [18,19,24]. However, most of the compounds in this series have not been examined in detail.…”

Section: Antiproliferative Activity Of Polysubstituted Pyrrolesmentioning

confidence: 99%

“…The synthetic methods used to prepare the highly functionalized pyrroles and related derivatives depicted in Scheme I can be found in previously reported work [19][20][21][22][23].…”

Section: Synthesis Of Pyrrole Compoundsmentioning

confidence: 99%

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Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Tripathi

Fornabaio

Kellogg

et al. 2008

Bioorganic & Medicinal Chemistry

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Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for eighteen polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of αβ-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r 2 of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Antiproliferative Activity Of Polysubstituted Pyrrolesmentioning

confidence: 99%

“…The synthetic methods used to prepare the highly functionalized pyrroles and related derivatives depicted in Scheme I can be found in previously reported work [19][20][21][22][23].…”

Section: Synthesis Of Pyrrole Compoundsmentioning

confidence: 99%

See 3 more Smart Citations

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Tripathi

Fornabaio

Kellogg

et al. 2008

Bioorganic & Medicinal Chemistry

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Synthesis and Cytotoxicity of Substituted Ethyl 2‐Phenacyl‐3‐phenylpyrrole‐4‐carboxylates

Evans

Smith

Holub

et al. 2003

Archiv der Pharmazie

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The substituted ethyl-2-phenacyl-3-phenylpyrrole-4-carboxylates were synthesized by a condensation of a beta-chloroenal and an alpha-aminoketone under neutral conditions. They proved to be potent cytotoxic agents against the growth of murine L1210 and P388 leukemias and human HL-60 promyelocytic leukemia, HuT-78 lymphoma, and HeLa-S(3) uterine carcinoma. Selective compounds were active against the growth of Tmolt(3) and Tmolt(4) leukemias and THP-1 acute monocytic leukemia, liver Hepe-2, ovary 1-A9, ileum HCT-8 adenocarcinoma, and osteosarcoma HSO. A mode of action study in HL-60 cells demonstrated that DNA and protein syntheses were inhibited after 60 min at 100 microM. DNA and RNA polymerases, PRPP-amido transferase, dihydrofolate reductase, thymidylate synthase, and TMP kinase activities were interfered with by the agent with reduction of d[NTP] pools. Nonspecific interaction with the bases of DNA and cross-linking of the DNA may play a role in the mode of action of these carboxylates.

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Pyrrole Natural Products with Antitumor Properties

Gupton

Topics in Heterocyclic Chemistry

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Synthesis and Cytotoxicity of 2,4-Disubstituted and 2,3,4-Trisubstituted Brominated Pyrroles in Murine and Human Cultured Tumor Cells

Cited by 18 publications

References 23 publications

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Synthesis and Cytotoxicity of Substituted Ethyl 2‐Phenacyl‐3‐phenylpyrrole‐4‐carboxylates

Pyrrole Natural Products with Antitumor Properties

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