Evaluation Of Functional Analogs Of CC-1065 And The Duocarmycins ...

Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard Save Email Send to

• Clipboard
• My Bibliography
• Collections
• Citation manager

Display options Display options Format Abstract PubMed PMID

Save citation to file

Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel

Email citation

Subject: 1 selected item: 8081835 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel

Add to Collections

• Create a new collection
• Add to an existing collection

Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel

Add to My Bibliography

• My Bibliography

Unable to load your delegates due to an error Please try again Add Cancel

Your saved search

Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons

• Yes
• No

Email: (change) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel

Create a file for external citation management software

Create file Cancel

Your RSS Feed

Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy

Full text links

Elsevier Science Full text links

Actions

CiteCollectionsAdd to Collections

• Create a new collection
• Add to an existing collection

Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an errorPlease try again Add Cancel Display options Display options Format AbstractPubMedPMID

Share

• Permalink Copy

Page navigation

• Title & authors
• Abstract
• Similar articles
• Cited by
• Publication types
• MeSH terms
• Substances
• Related information
• Grants and funding
• LinkOut - more resources

Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information Grants and funding LinkOut - more resources Full text links CiteDisplay options Display options Format AbstractPubMedPMID

Abstract

The DNA alkylation properties and in vitro cytotoxic activity of a series of analogs of CC-1065 and the duocarmycins incorporating the 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (C2BI) alkylation subunit are detailed. The C2BI-based agents have been shown to alkylate DNA within the minor groove in a fashion analogous to CC-1065 or duocarmycin. The stereoelectronically-controlled adenine N3 addition to the least substituted cyclopropane carbon occurs with a selectivity that represents a composite of the two enantiomers of the corresponding CBI-based agents. Additional high affinity alkylation sites were detected which were not prominent alkylation sites for either enantiomer of the CBI-based agents. Such sites may represent induced high affinity alkylation sites resulting from DNA cross-linking following complementary strand alkylation at a high affinity alkylation site and each such site detected proved consistent with predicted models of an adenine-adenine cross-linking event. Further, consistent with this interpretation, the C2BI agents were shown to constitute efficient cross-linking agents with DNA cross-linking being observed at the same concentrations as DNA alkylation. In comparison to the parent CBI-based agents, the C2BI-based agents proved to be approximately 100-10,000x less effective at DNA alkylation and 100-10,000x less potent in cytotoxic assays. This is suggested to be the consequence of a significant steric deceleration of the adenine N3 alkylation reaction attributable to the additional 9a-chloromethyl substituent. Consistent with this interpretation, the noncovalent binding constant of C2BI-CDPI2 for poly[dA]-poly[dA]-poly[dT] proved nearly identical to that of CDPI3 under kinetic binding conditions, and prolonged incubation of C2BI-CDPI2 with poly[dA]-poly[dT] (72 h, 25 degrees C) provided covalent complexes with a helix stabilization comparable to that observed with (+)- or (-)-CPI-CDPI2 indicating that the size of the C2BI subunit inhibits but does not preclude productive DNA alkylation.

PubMed Disclaimer

Similar articles

• CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents. Boger DL, Johnson DS. Boger DL, et al. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3642-9. doi: 10.1073/pnas.92.9.3642. Proc Natl Acad Sci U S A. 1995. PMID: 7731958 Free PMC article. Review.
• Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity. Boger DL, Johnson DS, Yun W, Tarby CM. Boger DL, et al. Bioorg Med Chem. 1994 Feb;2(2):115-35. doi: 10.1016/s0968-0896(00)82007-6. Bioorg Med Chem. 1994. PMID: 7922122
• 1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogs of CC-1065 and the duocarmycins: synthesis and evaluation. Boger DL, Yun W, Han N. Boger DL, et al. Bioorg Med Chem. 1995 Nov;3(11):1429-53. doi: 10.1016/0968-0896(95)00130-9. Bioorg Med Chem. 1995. PMID: 8634824
• Synthesis, chemical properties, and biological evaluation of CC-1065 and duocarmycin analogues incorporating the 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa. Boger DL, Hughes TV, Hedrick MP. Boger DL, et al. J Org Chem. 2001 Apr 6;66(7):2207-16. doi: 10.1021/jo001772g. J Org Chem. 2001. PMID: 11281757
• Recent developments in sequence selective minor groove DNA effectors. Reddy BS, Sharma SK, Lown JW. Reddy BS, et al. Curr Med Chem. 2001 Apr;8(5):475-508. doi: 10.2174/0929867003373292. Curr Med Chem. 2001. PMID: 11281837 Review.

See all similar articles

Cited by

• Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs. Díaz-Rodríguez E, Gandullo-Sánchez L, Ocaña A, Pandiella A. Díaz-Rodríguez E, et al. Cancers (Basel). 2021 Dec 29;14(1):154. doi: 10.3390/cancers14010154. Cancers (Basel). 2021. PMID: 35008318 Free PMC article. Review.
• The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface. Boger DL. Boger DL. J Org Chem. 2017 Dec 1;82(23):11961-11980. doi: 10.1021/acs.joc.7b02088. Epub 2017 Oct 13. J Org Chem. 2017. PMID: 28945374 Free PMC article.
• Synthesis and characterization of a cyclobutane duocarmycin derivative incorporating the 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (CbBI) alkylation subunit. Lajiness JP, Boger DL. Lajiness JP, et al. J Am Chem Soc. 2010 Oct 6;132(39):13936-40. doi: 10.1021/ja106986f. J Am Chem Soc. 2010. PMID: 20839806 Free PMC article.
• Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer. Tichenor MS, Trzupek JD, Kastrinsky DB, Shiga F, Hwang I, Boger DL. Tichenor MS, et al. J Am Chem Soc. 2006 Dec 13;128(49):15683-96. doi: 10.1021/ja064228j. J Am Chem Soc. 2006. PMID: 17147378 Free PMC article.
• CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents. Boger DL, Johnson DS. Boger DL, et al. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3642-9. doi: 10.1073/pnas.92.9.3642. Proc Natl Acad Sci U S A. 1995. PMID: 7731958 Free PMC article. Review.

Publication types

• Research Support, U.S. Gov't, P.H.S. Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search

MeSH terms

• Alkylation Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Antibiotics, Antineoplastic / chemistry* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Antibiotics, Antineoplastic / toxicity Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Base Composition Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Base Sequence Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Binding Sites Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Cross-Linking Reagents Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• DNA / chemistry Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Duocarmycins Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Electrophoresis, Polyacrylamide Gel Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Indoles* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Leucomycins / chemistry* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Leucomycins / toxicity Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Magnetic Resonance Spectroscopy Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Molecular Sequence Data Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Nucleic Acid Denaturation Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Pyrrolidinones / chemistry Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search

Substances

• 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Antibiotics, Antineoplastic Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Cross-Linking Reagents Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Duocarmycins Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Indoles Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Leucomycins Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Pyrrolidinones Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• CC 1065 Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• DNA Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• duocarmycin A Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search

Related information

• PubChem Compound (MeSH Keyword)

Grants and funding

• CA41986/CA/NCI NIH HHS/United States
• CA55276/CA/NCI NIH HHS/United States

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

Full text links [x] Elsevier Science [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To

• Clipboard
• Email
• Save
• My Bibliography
• Collections
• Citation Manager

[x]

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.