Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity

Abstract

A series of novel pyrrolo-allocolchicine derivatives (containing a 1-methyl-1H-indol-5-yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki-Miyaura cross-coupling of a 1-methylindole-5-boronate with an ortho-iodo-dihydrocinnamic acid derivative and subsequent intramolecular Friedel-Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu-type reaction by using zinc azide followed by LiAlH(4) reduction. Structural assignments were supported by X-ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub-nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines.

Synthesis of Indole‐Derived Allocolchicine Congeners through Pd‐Catalyzed Intramolecular C‐H Arylation Reaction

“…The geometric parameters of 20 and 34 were found to be considerably different. The dihedral angle between aromatic fragments A and B (see Figure 4) was determined as 43.0° for 20 and 32.3° for 34 , relative to 54° for colchicine ( 1 )45 and 47° for 7 (X = O) 9. These data suggest that compound 34 does not meet the basic structural requirements for interaction with the colchicine binding site of tubulin,3d whereas 20 shows structural similarity with highly active 7 (X = O).…”

“…Dauban, Dodd, and co‐workers synthesized a series of C5‐alkylated indolobenzazepinones (for instance compound 5 ) related to allocolchicine ( 2 ), some of which exhibited potent antimitotic activity across a wide panel of cancer‐cell lines. In the course of our own research into colchicinoids, we recently described the synthesis of indole‐derived allocolchicine analogs 6 and 7 9. These compounds exhibited strong antiproliferative and apoptosis‐inducing activities (at nanomolar or even sub‐nanomolar concentrations) against Burkitt‐like lymphoma (BJAB) cells, although their unspecific cytotoxicity was found to be particularly low.…”

Synthesis of indole-derived allocolchicine congeners exhibiting pronounced anti-proliferative and apoptosis-inducing properties

“…Recently, our group reported on the synthesis and biological evaluation of a series of heterocyclic allocolchicine congeners (for instance 3 and 4; Figure 1), in which ring C of the parent compound 2 is replaced by an indole 28,29 or a benzofurane 30 pharmacophore. 28 Herein, we report on the synthesis of pyrrolo-allocolchicinoids of type 5, i.e. 28 Herein, we report on the synthesis of pyrrolo-allocolchicinoids of type 5, i.e.…”

Synthesis of Nonracemic Pyrrolo‐allocolchicinoids Exhibiting Potent Cytotoxic Activity

“…Several structurally related compounds, such as allocolchicine ( 2 ), ( Z )‐stilbenes, 4‐arylcoumarins, and related compounds, were shown to exhibit pronounced cytotoxic effects (Figure ). In this context, we recently demonstrated that compounds 3 and rac ‐ 4 , with an extra furan or pyrrole unit annealed to ring C of the allocolchicine skeleton, exhibit unique antitumor activity …”

“…Notably, furano‐allocolchicinoid 3 inhibits tumor growth in mice without noticeable negative neurological symptoms, weight loss, or lethality of experimental animals . (Racemic) pyrrolo‐allocolchicinoid rac ‐ 4 demonstrated a high level of proliferation inhibition and apoptosis induction against different lymphoma cells, whereas its unspecific cytotoxicity is relatively low …”