Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids

Abstract

The full details for our enantioselective total syntheses of (−)-agelastatins A–F (1–6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (−)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (−)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure activity relationship within the natural series. Significantly, (−)-agelastatin A (1) is highly potent against six blood cancer cell lines (20–190 nM) without affecting normal red blood cells (>333 μM). (−)-Agelastatin A (1) and (−)-agelastatin D (4), the two most potent members of this family, induce dose dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy we have determined that neither alkaloid affects tubulin dynamics within cells.

Methods for the synthesis of 1-substituted 1H-imidazol-2(3H)-ones

“…Phenylurea (3a) does not undergo analogous transformation. It has been proposed 16 that the cyclization is affected by steric and electronic factors. In this case, the intermediate D (analogous to intermediate С, Scheme 2) reacts with the second molecule of phenylurea (3b), forming amide E, which disproportionates to diphenylurea 4a and 4,5-diphenyl-1H-imidazol-2(3H)-one (5a) (Scheme 3).…”

Electrophilic carbonyl activation: competing condensative cyclizations of tryptamine derivatives

“…As a continuation of our prior studies on the oxidation, rearrangement 9,12 and cyclization 13 of 2-aryltryptamines, we were intrigued by the possibility of accessing potentially three unique modes of cyclization of 2-heteroaryltryptamine substrates in the presence of activated carbonyl electrophiles (Scheme 1). In our first attempt at evaluating the planned cyclization chemistry, we targeted 4-bromo-5,7-dimethoxyindole 14 and the tryptamine boronic ester 18 as the two coupling partners in the C–C bond-forming cross-coupling reaction (Scheme 3–4).…”

“…8 Our group has continued to pursue programs focused on the syntheses and study of bisindole alkaloids. 9, 10 In our unified strategy to the trigonoliimine natural products ( 1–3 ), a selective oxidation/stereo controlled cyclization of a bistryptamine heterodimer provided access to all known trigonoliimines. 9 In addition, our program in electrophilic amide activation 11 has provided an entry into the Aspidosperma alkaloids.…”

“…9, 10 In our unified strategy to the trigonoliimine natural products ( 1–3 ), a selective oxidation/stereo controlled cyclization of a bistryptamine heterodimer provided access to all known trigonoliimines. 9 In addition, our program in electrophilic amide activation 11 has provided an entry into the Aspidosperma alkaloids. 10 These studies have focused on the oxidation and cyclization of a variety of tryptamine substrates that occur primarily at the C2 and C3 positions.…”

“…10 These studies have focused on the oxidation and cyclization of a variety of tryptamine substrates that occur primarily at the C2 and C3 positions. The combination of our prior strategies for rapid synthesis of 2-(2'-indolyl)-tryptamines, 9 2-(7'-indolyl)-tryptamines, 12 and our interest in spirocyclization of tryptamines 13 provided a unique opportunity to examine the competing cyclization manifolds available to 2-(4'-indolyl)-tryptamine such as 5 (Scheme 1). Herein we present our studies on the cyclization reactions of bisindoles and detail our results in securing a challenging spirocyclization using a carbamoyl chloride substrate.…”