Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with ...tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein–protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.
Two conformationally restricted three-dimensional aminoketone scaffolds have been synthesized in only three steps, using a continuous flow photochemistry approach, which is also amenable to scale-up. ...In addition, several approaches to further derivatize these scaffolds for the synthesis of low molecular weight compound libraries have been detailed.
Iododecarboxylation of labdanolic acid (
1), followed by dehydrohalogenation led to alkenes
4 and
12. Both compounds were converted into (1
R,2
R,4a
S,8a
...S)-1-(2-hydroxyethyl)-2,5,5,8a-tetramethyldecahydro-2-naphthalenol (
8), which was transformed via cyclization into (−)-Ambrox
® (
9).
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The oxidation of the (3-hydroxy-3-methyl-4-pentenyl)-side chain at C(9) of some labdanic diterpenoids with potassium permanganate was investigated. Triols, ketones, or cyclic enol ethers are the main ...reaction products, strongly influenced by the substituent at C(8). Further degradation of the methyl ketones by the Baeyer–Villiger reaction and modification of the exocyclic 8(17) double bond lead to suitable intermediates, which have been transformed into Ambrox
®-like compounds. Synthetic routes using palladium catalyzed elimination or isomerization of allylic acetates, followed by ozonolysis have been developed as well for shortening of the side chain of (+)-larixol. Products from both routes have been cyclized to 6α-hydroxy Ambrox
®. This compound was used as the key intermediate for the synthesis of several other Ambrox
®-like compounds of which some showed pleasant odour properties.
Graphic
(+)-Larixol can be easily transformed into intermediates with an hydroxyl group at C(6), a Δ
7 double bond and a substituted side chain at C(9) with a second hydroxyl group. Abstraction of the ...allylic hydroxyl group at C(6), followed by interception of the resulting mesomeric carbocation at C(8) by the hydroxyl group in the side chain, allows the synthesis of some C(13) modified Δ
6-tricyclic tetrahydropyranyl ethers (Δ
6-Ambra oxides). The formation of Δ
6,8-dienes proves to be a seriously competing reaction.
Graphic
Several Ambrox®-like compounds were synthesized in an enantiomerically pure form, and in relatively short procedures, starting from (+)-larixol. Triol 5 and enone 6 are important intermediates in ...these syntheses. The formation of Δ6-Ambrox®-type ethers was achieved by a new cyclization approach via ionization of the C(6)-allylic alcohol in ring B.
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