Synthesis and Anti-Angiogenic Activity of Cortistatin Analogs

Cortistatin A is a High‐Affinity Ligand of Protein Kinases ROCK, CDK8, and CDK11

“…Our model suggests that loss of solvent‐exposed hydroxy groups is not likely to be detrimental to activity, but removal of the C3 basic amine could lead to an attenuation of ROCK binding, because of the proposed interaction of the amine with Asp 202 in ROCK (Ala 155 in CDK8). Kiyota and co‐workers3a were the first to report analogues based on a simplified estrane skeleton, and Corey and co‐workers have produced the most potent analogues in this structural class to date ( 13 , 14 ) 3c. These analogues show an interesting SAR with respect to the isoquinoline connectivity, with the 6‐substituted isoquinoline 14 showing better potency than the cortistatin A‐like 7‐substituted isoquinoline 13 .…”

Adventures in Total Synthesis: A Personal Account

“…We shall conclude our discussions with a few cursory remarks on the chemical biology of the cortistatins. Several research groups have reported SAR studies of the cortistatins, ranging from the estrone-derived analogue 87 and 88 disclosed by the Kiyota 49 and Corey groups, 50 to the more elaborate cortistatin derivatives 89 and 81 reported by Baran 51 and Nicolaou and Chen 38d and their co-workers (Figure 7). Furthermore, Cee et al demonstrated that cortistatin A (63) exhibited selective and high affinity binding to a small group of kinases, including CDK (cyclin-dependent kinase) 8, CDK11, ROCK (Rho-associated kinase) I, and ROCK II.…”

Pd-catalyzed Suzuki–Miyaura couplings and evaluation of 13α-estrone derivatives as potential anticancer agents

“…Literature reveals the application of Suzuki-Miyaura coupling in the synthesis of estrone derivatives with diverse biological activities. C-C couplings on the estrane core were carried out mainly at C-2, C-3, C-4 or C-17 [23][24][25][26][27][28][29]. Estrone derivatives such as aryl halides (at C-2 or C-4) or aryl or enol triflates (at C-3 or C-17) have been used.…”

“…However, Ciana et al developed a copper-catalyzed, site-selective C-H arylation methodology for the synthesis of 2-phenyl estrone derivatives [30]. Sato et al synthesized estrone-isoquinoline hybrids as cortistatin analogs with substantial anti-angiogenic properties [23]. 17-Pyridyl estrones have been prepared as effective AKR1C3 inhibitors, which might be promising drug candidates in the treatment of endometriosis.…”