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

Abstract

The synthesis of 1,2,10,11-tetrahydro-9H-cyclobuta [c]benzo [e]indol-4-one (17, CbBI), containing a deep-seated fundamental structural modification in the CC-1065 and duocarmycin alkylation subunit with the incorporation of a ring expanded fused cyclobutane (vs cyclopropane), its chemical and structural characterization, and its incorporation into a key analogue of the natural products are detailed. The approach to the preparation of CbBI was based on a precedented (Ar-3′ and Ar-5′), but previously unknown Ar-4′ spirocyclization of a phenol onto a tethered alkyl halide to form the desired cyclobutane. The conditions required for the implementation of the Ar-4′ spirocyclization indicate that the entropy of activation substantially impacts the rate of reaction relative to the much more facile Ar-3′ spirocyclization, while the higher enthalpy of activation slows the reaction relative to an Ar-5′ spirocyclization. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity, and a single crystal X-ray structure analysis of N-Boc-CbBI (13) revealed their structural origins. The reaction regioselectivity may be attributed to the stereoelectronic alignment of the two available cyclobutane bonds with the cyclohexadienone π-system, which resides in the bond that extends to the less substituted cyclobutane carbon for 13. The remarkable stability of N-Boc-CbBI (stable even at pH 1) relative to N-Boc-CBI (t 1/2 = 133 h at pH 3) containing a cyclopropane may be attributed to a combination of the increased extent of vinylogous amide conjugation, the nonoptimal geometric alignment of the cyclobutane with the activating cyclohexadienone, and the intrinsic but modestly lower strain energy (1.8 kcal/mol) of a cyclobutane versus cyclopropane.

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

“…In the course of these studies, we introduced a convenient M13-derived alternative to 32 P-end-labeling of restriction fragments for DNA cleavage studies . Fundamental relationships between structure and reactivity or structure and activity, and their contributions to the DNA alkylation properties and biological activity of the natural products, were established through the examination of more than 2000 analogues of the natural products that contained deep-seated structural changes (e.g., CBI). − A compilation of the data derived from more than 30 deep-seated modifications, many of which entailed single heavy atom changes, − resulted in the establishment of a predictive parabolic relationship between the alkylation subunit reactivity and the resulting cytotoxic potency that spanned a 10 4 –10 6 range of reactivity and activity (Figure ). − Presumably, this fundamental relationship reflects the fact that the compound must be sufficiently stable to reach its biological target yet remain sufficiently reactive to alkylate DNA once it does.…”

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

“…A recent controversial theory claims that duocarmycins act also by inhibiting aldehyde dehydrogenase 1, an enzyme target that plays important roles in the viability and detoxification of cancer cells (24)(25)(26). For ADCs applications, we have used duocarmycin analogues that had previously been shown to be more potent and more synthetically accessible than their naturally occurring counterpart (27).…”

Gold Catalysis Enabling Furan-Fused Cyclobutenes as a Platform toward Cross Cycloadditions

“…Polyheterocycles with a cyclobutane functionality at the fused junction are important structural motif in many natural products (I, II, III) and also behave as a new glycoluril diether, one kind of supramolecular precursors (IV) with a wide dihedral angle on the concave face (Scheme A). Classical procedures, such as [2π+2π]-photocycloaddition, ring-expansion of cyclopropane, nucleophilic ring-closure, transition-metal catalyzed cyclization, and so on, have been developed for the construction of cyclobutane-containing architecturally complex molecules. However, these methods have often suffered from inconvenient reaction conditions, low selectivities, and inaccessibility of substrates.…”