Photochemical Activation of Enediyne Warheads: A Potential Tool for Targeted Antitumor Therapy

Abstract

Spatial and temporal control over DNA cleavage by photoactivated enediynes can be complemented by additional factors such as the release of internal strain, chelation, pH changes, intramolecular H-bonds, and substituent effects. This review presents design and reactivity of photoactivated enediynes/enynes and analyses the chemical, biological, and photophysical challenges in their applications.

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

“…22 Numerous analogues of naturally occurring enediynes have been synthesized in search for anticancer agents among the enediyne family with simpler structure than natural enediynes, while maintaining high activity. [23][24][25][26][27] Quite simple N-containing analogues of sophisticated naturally occurring enediynes has been known since 1997 28 and represent an important class in the search for new anticancer drugs, because incorporation of an N atom into an enediyne cycle allowed structure-activity relationship to be varied and attenuated. [29][30][31][32][33][34][35][36] In all examples of enediyne synthesized except one 33 the nitrogen atom is in a homopropargylic position, therefore the Nicholas reaction could be a suitable method for a macrocyclization step.…”

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

“…The payload consists of four glycosidic units, a fully substituted iodobenzoate moiety, and an aglycon. The highly reactive hex-3-ene-1,5-diyne subunit can be readily triggered to aromatize via a Bergman cyclization reaction, generating a benzene-1,4-diradical [37]. This aromatization process affords a resulting diradical that can abstract two hydrogen atoms from the DNA backbone, leading to unrepairable double-strand (ds) DNA breaks followed by cell-cycle arrest and apoptotic cell death, see Figure 5 A crucial feature for successful construction of an ADC is the conjugation chemistry of the linker-payload with the mAb.…”

Synthesis and Biological Evaluation of Taurine‐Derived Diarylmethane and Dibenzoxanthene Derivatives as Possible Cytotoxic and Antimicrobial Agents

“…One of the promising approaches to the selective anti‐tumor drugs utilizes the higher acidity of an extracellular environment [13,14] of tumor tissues compared to normal ones. For example, this approach was used for the successful design of highly active DNA‐photocleavers combining enediyne moiety as the DNA cleaving agent and amino acids as the pH‐sensitive fragment [15,16] …”

“…In recent years, studies have appeared identifying the Taurolidine as potential anti‐cancer compound [27–29] . Moreover, a taurine molecule possesses two nitrogen atoms with different basicity, which was shown to be important for enhancing the pH‐ sensitivity of the ‘hybrid’ anti‐tumor agents [15,16] …”

“…For example, this approach was used for the successful design of highly active DNAphotocleavers combining enediyne moiety as the DNA cleaving agent and amino acids as the pH-sensitive fragment. [15,16] Earlier, we have developed the method of synthesis of polyphenolic diarylmethane derivatives and closely related dibenzoxanthenes based on the acid-catalyzed reaction of nitrogen-containing acetals with various phenols. [17][18][19] We speculated that the introduction of the pH-sensitive moieties into the structure of these compounds may also increase their selectivity towards tumor cell lines.…”