5074-58-8

Upstream product

• 71748-23-7 17-hydroxy-2-methoxy-17,18-cyclo-corynox-1-ene-16-carboxylic acid methyl ester 
• 36193-50-7 17-hydroxy-2-methoxy-17,18-cyclo-corynox-1-ene-16-carboxylic acid methyl ester 
• 146-48-5 Yohimbine 
• 33352-70-4 7-chloro-17-hydroxy-2,7-dihydro-yohimb-1-ene-16-carboxylic acid methyl ester 
• 94992-42-4 (1R,2S,4aR,8aR,13bS,14aS)-8a-Chloro-2-hydroxy-1,2,3,4,4a,5,7,8,8a,13b,14,14a-dodecahydro-indolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylic acid methyl ester 
• 94992-41-3 (1R,2S,4aR,8aS,13bS,14aS)-8a-Chloro-2-hydroxy-1,2,3,4,4a,5,7,8,8a,13b,14,14a-dodecahydro-indolo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylic acid methyl ester 

Relevant academic research and scientific papers

A Tryptoline Ring-Distortion Strategy Leads to Complex and Diverse Biologically Active Molecules from the Indole Alkaloid Yohimbine

High-throughput screening (HTS) is the primary driver to current drug-discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have a low fraction of sp3 character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e.g., transcription factors) have largely evaded the discovery of new clinical agents from screening collections. Herein, a tryptoline ring-distortion strategy is described that enables the rapid synthesis of 70 complex and diverse compounds from yohimbine (1); an indole alkaloid. The compounds that were synthesized had architecturally complex and unique scaffolds, unlike 1 and other scaffolds. These compounds were subjected to phenotypic screens and reporter gene assays, leading to the identification of new compounds that possessed various biological activities, including antiproliferative activities against cancer cells with functional hypoxia-inducible factors, nitric oxide inhibition, and inhibition and activation of the antioxidant response element. This tryptoline ring-distortion strategy can begin to address diversity problems in screening libraries, while occupying biologically relevant chemical space in areas critical to human health.

ANALOGS OF YOHIMBINE AND USES THEREOF

The present disclosure provides compounds of Formulae (I-A), (ΙI'), (III-A), (IV'), and (V-A), wherein the compounds are derived from or based on yohimbine. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, cancers, inflammatory diseases, autoimmune diseases, and infectious diseases) in a subject in need thereof. The present disclosure provides methods of preparing compounds of Formulae (I-A), (ΙI'), (III-A), (IV'), and (V-A). Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

A reinvestigation of the oxidative rearrangement of yohimbane-type alkaloids. Part B. Formation of oxindol (= 1,3-dihydro-2H-indol-2-one) derivatives

The methanolysis of the epimeric 7-chloro-7H-yohimbine derivatives 2 and 3 was reinvestigated. In case of the 7α-epimer 2, the reaction was uneventful and conformed with earlier observations, i.e., under sufficiently mild conditions, only the imino ether 4 (= imino ether A) was produced. Under the same conditions, the less reactive β-isomer 3 furnished a mixture of both imino ethers 4 and 5, accompanied by the elimination product 11, and by equal amounts of yohimbine (1) and 3,4,5,6-tetradehydroyohimbine (12), which are believed to arise through a disproportionation process of the putative intermediate 5,6-didehydroyohimbine (23). The nature of this divergent reactivity and of the ready equilibration of 4 and 5 was investigated by means of extensive force-field and semi-empirical calculations (AM1 and PM3) of various conformers of the compounds 2-5 and of some possible reaction intermediates.