Total synthesis of (+)-duocarmycin SA

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

“…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).…”

Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) alkylation subunit

“…35 The alkylation site identification and the assessment of the relative selectivity among the available sites were obtained by thermally-induced strand cleavage of the singly 5′-end-labeled duplex DNA after exposure to the compounds as detailed. 35 The examination of (+)-CImI-TMI ( 16 ), conducted with the equivalent seco precursor 15 , demonstrated that it alkylated the same single site as (+)-duocarmycin SA in w794, displaying the same characteristic DNA alkylation selectivity (Figure 5). In addition, the natural enantiomer (+)- 16 alkylated DNA with an efficiency only 2-fold less than (+)-duocarmycin SA (data not shown), consistent with its 5-fold less potent cytotoxic activity.…”

Asymmetric Synthesis of 1,2,9,9a-Tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)

“…Most significantly, its derivative analogues were found to be 4-fold more stable and 4-fold more potent than the corresponding analogues bearing the 7-MeCPI subunit found in CC-1065 and to display a substantially enhanced intrinsic reaction regioselectivity (>20:1 vs 4–6:1) 9. Additionally, its derivative analogues were found to alkylate DNA with an unaltered sequence selectivity at enhanced rates and with a greater efficiency than the corresponding 7-MeCPI analogues 10. Although not quite as potent as the corresponding duocarmycin SA analogues, the ability to easily prepare and evaluate CBI analogues designed to probe fundamental questions on structure, reactivity, and activity have resulted in its extensive use 6.…”