A Scalable Process for the Synthesis of the Bcl Inhibitor Obatoclax

Abstract

Recently we created the novel indolylprodigiosin derivative 2 (obatoclax) and demonstrated its ability to antagonize multiple members of the B-cell lymphoma (Bcl) family of antiapoptotic proteins. The compound has shown potent anticancer activity in several animal tumor models. Obatoclax is now in Phase 1b and 2 clinical trials directed against multiple hematologic and solid tumor malignancies. To support its clinical development, a new scalable synthesis was required. Obatoclax has been prepared using a three-step synthesis, starting from commercially available 4-methoxy-3-pyrrolin-2-one. The reaction sequence involves a haloformylation reaction followed by a Suzuki cross-coupling reaction with an indole-2-boronic acid. The synthesis is completed by an acid-mediated condensation with 2,4-dimethyl-1H-pyrrole.

Synthetic Prodiginine Obatoclax (GX15‐070) and Related Analogues: Anion Binding, Transmembrane Transport, and Cytotoxicity Properties

“…Synthesis and anion-binding studies: Compounds 1 a-c were synthesized by using variations on reported procedures (Scheme 1). [10] Briefly, acid-catalyzed condensation of indole-pyrrole aldehyde 6 with assorted pyrroles gave 1 a and analogues 1 b and 1 c in good yields. Small amounts of a symmetrical derivative 2 were also detected in the reaction mixtures.…”

Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products

“…This process has been used by Gemin X to prepare multikilogram quantities of a synthetic prodigiosin analogue, obatoclax, for clinical trials. 33 …”

“…8,20–27 A synthetic analogue based on the prodiginine family, obatoclax, was used in multiple phase I and II combination cancer chemotherapy studies. 28–33 The quorum sensing control of prodigiosin biosynthesis and medicinal properties of the prodiginines have been previously reviewed. 3,8,24,34,35 …”

Small-Molecule Inhibitors Reveal a New Function for Bcl-2 as a Proangiogenic Signaling Molecule

“…A candidate for earliest patented small molecule inhibitor of Bcl-2 is Obatoclax (GX15-070) (Figure 2D) developed by Gemin X Biotechnologies Inc. from derivatives of the bacterially derived streptorubin B (Daïri et al 2007; Shore and Viallet. 2005).…”

“…This approach to screen for broad functional inhibition of BH3-only binding led to the development of a true pan-Bcl-2 inhibitor. In similar fashion, Obatoclax (GX15-070) was rationally designed to fit the Bcl-2 BH3-binding domain in competition with pro-apoptotic Bax (Daïri et al 2007). It was developed using structural data obtained from the bacterial derivative Streptorubin B.…”