2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d] pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance

Aleem Gangjee, Ojas A. Namjoshi, Staci N. Keller, Charles D. Smith

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5- phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P-glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1) mediated tumor resistance (unlike the Vinca alkaloids and taxanes). Some of these compounds, in addition to their antitumor activity, had the ability to reverse the Pgp-mediated resistance to clinically used antimitotic agents. This report consists of an attempt to optimize the various activities of the parent compounds by synthetic variations of the phenyl ring of the 5-phenylethyl side chain. The target compounds were synthesized via a nine-step synthesis involving a Sonogashira reaction. The substituted phenylacetylenes as coupling partners were in turn synthesized from unactivated aryl bromides or iodides. The target compounds exhibited moderate cytotoxicity against MCF-7 tumor cells. However, most of these compounds showed improved cytotoxicity against the resistant NCI/ADR and MCF-7/VP. This study afforded an analog which reversed both Pgp-mediated as well as MRP1-mediated resistance to clinically used antimitotic agents, along with its own antimitotic mediated antitumor activity. In addition, in the NCI-60 cell line panel one of the compounds inhibited the growth of MDA-MD-435 breast cancer cell line at submicromolar concentration.

Original languageEnglish (US)
Pages (from-to)4355-4365
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number14
DOIs
StatePublished - Jul 15 2011

Fingerprint

Antimitotic Agents
P-Glycoprotein
Antineoplastic Agents
Tumors
Cells
Neoplasms
Cytotoxicity
Vinca Alkaloids
Viral Structural Proteins
Cell Line
Taxoids
MCF-7 Cells
Iodides
Bromides
Pyrrolo(2,3-d)pyrimidine
Breast Neoplasms
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

@article{77c51ad9be074bc9ab39389eea5f571c,
title = "2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d] pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance",
abstract = "Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5- phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P-glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1) mediated tumor resistance (unlike the Vinca alkaloids and taxanes). Some of these compounds, in addition to their antitumor activity, had the ability to reverse the Pgp-mediated resistance to clinically used antimitotic agents. This report consists of an attempt to optimize the various activities of the parent compounds by synthetic variations of the phenyl ring of the 5-phenylethyl side chain. The target compounds were synthesized via a nine-step synthesis involving a Sonogashira reaction. The substituted phenylacetylenes as coupling partners were in turn synthesized from unactivated aryl bromides or iodides. The target compounds exhibited moderate cytotoxicity against MCF-7 tumor cells. However, most of these compounds showed improved cytotoxicity against the resistant NCI/ADR and MCF-7/VP. This study afforded an analog which reversed both Pgp-mediated as well as MRP1-mediated resistance to clinically used antimitotic agents, along with its own antimitotic mediated antitumor activity. In addition, in the NCI-60 cell line panel one of the compounds inhibited the growth of MDA-MD-435 breast cancer cell line at submicromolar concentration.",
author = "Aleem Gangjee and Namjoshi, {Ojas A.} and Keller, {Staci N.} and Smith, {Charles D.}",
year = "2011",
month = "7",
day = "15",
doi = "10.1016/j.bmc.2011.05.030",
language = "English (US)",
volume = "19",
pages = "4355--4365",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "14",

}

2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d] pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance. / Gangjee, Aleem; Namjoshi, Ojas A.; Keller, Staci N.; Smith, Charles D.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 14, 15.07.2011, p. 4355-4365.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d] pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance

AU - Gangjee, Aleem

AU - Namjoshi, Ojas A.

AU - Keller, Staci N.

AU - Smith, Charles D.

PY - 2011/7/15

Y1 - 2011/7/15

N2 - Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5- phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P-glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1) mediated tumor resistance (unlike the Vinca alkaloids and taxanes). Some of these compounds, in addition to their antitumor activity, had the ability to reverse the Pgp-mediated resistance to clinically used antimitotic agents. This report consists of an attempt to optimize the various activities of the parent compounds by synthetic variations of the phenyl ring of the 5-phenylethyl side chain. The target compounds were synthesized via a nine-step synthesis involving a Sonogashira reaction. The substituted phenylacetylenes as coupling partners were in turn synthesized from unactivated aryl bromides or iodides. The target compounds exhibited moderate cytotoxicity against MCF-7 tumor cells. However, most of these compounds showed improved cytotoxicity against the resistant NCI/ADR and MCF-7/VP. This study afforded an analog which reversed both Pgp-mediated as well as MRP1-mediated resistance to clinically used antimitotic agents, along with its own antimitotic mediated antitumor activity. In addition, in the NCI-60 cell line panel one of the compounds inhibited the growth of MDA-MD-435 breast cancer cell line at submicromolar concentration.

AB - Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5- phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P-glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1) mediated tumor resistance (unlike the Vinca alkaloids and taxanes). Some of these compounds, in addition to their antitumor activity, had the ability to reverse the Pgp-mediated resistance to clinically used antimitotic agents. This report consists of an attempt to optimize the various activities of the parent compounds by synthetic variations of the phenyl ring of the 5-phenylethyl side chain. The target compounds were synthesized via a nine-step synthesis involving a Sonogashira reaction. The substituted phenylacetylenes as coupling partners were in turn synthesized from unactivated aryl bromides or iodides. The target compounds exhibited moderate cytotoxicity against MCF-7 tumor cells. However, most of these compounds showed improved cytotoxicity against the resistant NCI/ADR and MCF-7/VP. This study afforded an analog which reversed both Pgp-mediated as well as MRP1-mediated resistance to clinically used antimitotic agents, along with its own antimitotic mediated antitumor activity. In addition, in the NCI-60 cell line panel one of the compounds inhibited the growth of MDA-MD-435 breast cancer cell line at submicromolar concentration.

UR - http://www.scopus.com/inward/record.url?scp=79959945184&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959945184&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2011.05.030

DO - 10.1016/j.bmc.2011.05.030

M3 - Article

C2 - 21680190

AN - SCOPUS:79959945184

VL - 19

SP - 4355

EP - 4365

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 14

ER -