An improved synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI): a simplified analog of the CC-1065 alkylation subunit

Boger, Dale L.; Yun, Weiya; Teegarden, Bradley R.

doi:10.1021/jo00036a023

Cited by 73 publications

(49 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the observations are inconsistent with alternative models based on the premise that the natural enantiomer alkylation subunit controls the alkylation selectivity. Similarly, the unnatural enantiomer of the reversed agent ent-(-)-CDPI2-DSA (26) was found to alkylate the same sites as (+)-DSA-CDPI2 (25) [77][78][79], and the extensive number of investigations directed at the subunits of the natural products (33), studies that have provided analogs (80,81) and agents containing deepseated structural modifications have proven unusually valuable in defining the relationships between structure, functional reactivity, and biological properties (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97). The acid-catalyzed activation of the DNA alkylation reaction led to the intuitive proposal that there may exist a direct relationship between the reactivity and cytotoxic activity of the agents and established the expectation that the biological potency may be enhanced as the electrophilic reactivity is increased (81).…”

mentioning

confidence: 99%

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Boger

Johnson

1995

Proc. Natl. Acad. Sci. U.S.A.

212

100

View full text Add to dashboard Cite

Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronicaily controlled adenine-N3

show abstract

mentioning

confidence: 99%

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Boger

Johnson

1995

Proc. Natl. Acad. Sci. U.S.A.

212

100

View full text Add to dashboard Cite

show abstract

“…Schließlich beschrieben Boger und Mitarbeiter die Synthese eines synthetisch besser zugänglichen Cyclopropabenzindols (CBI, Abbildung 27) als Mçglichkeit, um die alkylierende CPI-Untereinheit zu ersetzen und dabei zu Verbindungen zu gelangen, die noch immer aktiv waren, aber etwa 4-mal so stabil. [99][100][101] Versuche, diese neuen Gruppen einzubauen, wurden zunächst mit der Synthese des Analogons DC1 umgesetzt, das das stabilere Chlormethyl-Surrogat, CBI als alkylierende Untereinheit und einen Linker mit einem Thiol an der terminalen Pyrroloindol-Einheit für die Konjugation mit einem Antikçrper enthält (Abbildung 30). [102] Antikçrper-DC1-Konjugate mit 3 bis 4 DC1-Molekülen pro Antikçrper und Disulfidbrücken erwiesen sich als extrem cytotoxisch mit IC 50 -Werten im niedrigen pikomolaren Bereich und mit einer > 1000fachen Selektivität für antigen-positive Zellen.…”

Section: (+)-Cc-1065 Und Die Duocarmycine Als Adc-beladungunclassified

Antikörper‐Wirkstoff‐Konjugate: ein neues Konzept in der Krebstherapie

2014

View full text Add to dashboard Cite

Herkömmliche Chemotherapeutika gegen Krebs gehen oft mit einer systemischen Toxizität im Patienten einher. Einen alternativen, tumorselektiven Behandlungsansatz bieten monoklonale Antikörper gegen Antigene oder Krebszellen. Allerdings sind die meisten monoklonalen Antikörper nicht wirksam genug, um allein für sich therapeutisch aktiv zu sein. Antikörper‐Wirkstoff‐Konjugate (ADCs) verwenden Antikörper, um eine potente cytotoxische Verbindung selektiv zu Tumorzellen zu befördern, und erhöhen so die therapeutische Breite chemotherapeutischer Wirkstoffe. Die kürzlich erfolgte Zulassung zweier ADCs, Brentuximab Vedotin und Ado‐Trastuzumab Emtansin, zur Krebsbehandlung hat dem Forschungsinteresse auf diesem Gebiet weiteren Schub verliehen. Dieser Aufsatz beschreibt, wie die Erkenntnisse aus Studien an den ADCs der ersten Generation zu erfolgreichen Verbesserungen aller Komponenten – Antikörper, cytotoxische Verbindung und Linker – geführt haben. Die Ausgestaltung von in der klinischen Entwicklung befindlichen ADCs sowie Ergebnisse mechanistischer Studien und präklinischer und klinischer Tests werden diskutiert, ebenso wie neu aufkommende Technologien, die zu weiteren Fortschritten in diesen aufregenden Gebiet führen werden.

show abstract

“…We have developed functionalized Py À Im polyamides that target specific DNA sequences and evaluated their biological properties. [4] PyÀIm polyamide conjugates with the 1,2,9,9a-tetra-hydrocyclopropaA C H T U N G T R E N N U N G [1,2-c]benzA C H T U N G T R E N N U N G [1,2-e]indol-4-one (CBI) [5][6][7] alkylating moiety have sequence-specific DNA-alkylating activity to alkylate at the N3 position of adenine at a predetermined site. [8] In particular, we have successfully targeted and induced sequence-specific alkylation at the Kras codon 13 mutation site.…”

mentioning

confidence: 99%

Sequence‐Specific DNA Alkylation by Tandem Py–Im Polyamide Conjugates

Taylor

Kawamoto

Hashiya

et al. 2014

Chemistry An Asian Journal

View full text Add to dashboard Cite

Tandem N-methylpyrrole-N-methylimidazole (Py-Im) polyamides with good sequence-specific DNA-alkylating activities have been designed and synthesized. Three alkylating tandem Py-Im polyamides with different linkers, which each contained the same moiety for the recognition of a 10 bp DNA sequence, were evaluated for their reactivity and selectivity by DNA alkylation, using high-resolution denaturing gel electrophoresis. All three conjugates displayed high reactivities for the target sequence. In particular, polyamide 1, which contained a β-alanine linker, displayed the most-selective sequence-specific alkylation towards the target 10 bp DNA sequence. The tandem Py-Im polyamide conjugates displayed greater sequence-specific DNA alkylation than conventional hairpin Py-Im polyamide conjugates (4 and 5). For further research, the design of tandem Py-Im polyamide conjugates could play an important role in targeting specific gene sequences.

show abstract

An improved synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI): a simplified analog of the CC-1065 alkylation subunit

Cited by 73 publications

References 0 publications

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Antikörper‐Wirkstoff‐Konjugate: ein neues Konzept in der Krebstherapie

Sequence‐Specific DNA Alkylation by Tandem Py–Im Polyamide Conjugates

Contact Info

Product

Resources

About