Wolfgang Dohle

Synthesis of polyfunctional indoles and related heterocycles mediated by cesium and potassium bases

A general preparation of 2-substituted indoles starting from functionalized 2-alkynylanilines has been developed. This base mediated reaction has also been used to synthesize the heterocyclic core of the marine alkaloid hinckdentine A. Furthermore the reaction was successfully adapted to the solid phase. Benzofurans and isoindolones could also be prepared with this method.

A protecting group free synthesis of (+/-)-neostenine via the [5 + 2] photocycloaddition of maleimides.

A concise, linear synthesis of the Stemona alkaloid (+/-)-neostenine is reported. Key features include an organocopper-mediated bislactone C2-desymmetrization for the stereoselective construction of the cyclohexane-lactone C,D-rings. The assembly of the fused pyrrolo[1,2-a]azepine core was achieved by application of a [5 + 2] maleimide photocycloaddition. A custom FEP flow reactor was used to successfully overcome the scale limitations imposed by a classical immersion well batch reactor. The synthesis was completed in 14 steps from furan, in 9.5% overall yield, without the use of any protecting groups.

Synthesis, Antitubulin, and Antiproliferative SAR of Analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate

The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH(2) with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.

Improved Nickel-Catalyzed Cross-Coupling Reaction Conditions between ortho-Substituted Aryl Iodides/Nonaflates and Alkylzinc Iodides in Solution and in the Solid-Phase

Abstract ortho-Substituted aryl iodides and nonaflates undergo nickel-catalyzed cross-coupling reactions with functionalized alkylzinc iodides in the solid-phase as well as in solution providing high HPLC purities and good yields.

Structure–Activity Relationships of C-17-Substituted Estratriene-3-O-sulfamates as Anticancer Agents

The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17β-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity.

Functionalized main-group organometallics for organic synthesis*

Highly functionalized Grignard-reagents can be easily obtained by an iodinemagnesim exchange reaction and further reacted with various electrophiles. Via a BZn exchange reaction, a formal Michael addition with umpolung of the reactivity can be achieved. Chiral phosphine ligands can be easily synthesized by a 2.3 sigmatropic rearrangement and used successfully in asymmetric synthesis.

Synthesis, antitubulin, and antiproliferative SAR of C3/C1-substituted tetrahydroisoquinolines.

The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl‐substituted sulfamate (±)‐7‐methoxy‐2‐(3‐methoxybenzyl)‐3‐methyl‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (6u2009b), for example, was found to be ∼10‐fold more potent than the corresponding non‐methylated compound 7‐methoxy‐2‐(3‐methoxybenzyl)‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (4u2009b) against DU‐145 prostate cancer cells (GI50 values: 220u2005nM and 2.1u2005μM, respectively). Such compounds were also found to be active against a drug‐resistant MCF breast cancer cell line. The position and nature of substitution of the N‐benzyl group in the C3‐substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3‐gem‐dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study.

Optimisation of tetrahydroisoquinoline-based chimeric microtubule disruptors.

Tetrahydroisoquinoline (THIQ)‐based “chimeric” microtubule disruptors were optimised through modification of the N‐benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15: GI50 20u2005nM in DU‐145). The broad anticancer activity of these novel structures was confirmed in the NCI 60‐cell line assay, with 12u2009e,f displaying MGM values in the 40u2005nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8u2005μM, close to that of the clinical drug combretastatin A‐4, and also proved effective at blocking colchicine binding. Additionally, compound 20u2009b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50=1.6u2005μM). Compound 12u2009f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.

Tetrahydroisoquinolinone-Based Steroidomimetic and Chimeric Microtubule Disruptors

A structure–activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)‐based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B‐ring‐mimicking THIQ core was connected to methoxyaryl D‐ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7‐methoxy‐2‐(3‐ methoxybenzyl)‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (20u2009c) GI50=2.1u2005μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ‐based A,B‐mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40u2005nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7‐methoxy‐6‐sulfamoyloxy‐2‐(3,4,5‐trimethoxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (20u2009z) relative to a benchmark steroidal bis‐ sulfamate in an in vivo model of multiple myeloma.

Synthesis, anti-tubulin and antiproliferative SAR of steroidomimetic dihydroisoquinolinones

A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)‐based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)‐based compounds. A steroid A,B‐ring‐mimicking DHIQ core was connected to methoxyaryl D‐ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl‐linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6‐hydroxy‐7‐methoxy‐2‐(3,4,5‐trimethoxybenzoyl)‐3,4‐dihydroisoquinolin‐1(2H)‐one (16u2009g): GI50 51u2005nM in DU‐145 cells). The broad anticancer activity of DHIQ 16u2009g was confirmed in the NCI 60‐cell line assay giving a mean activity of 33u2005nM. Furthermore, 6‐hydroxy‐2‐(3,5‐dimethoxybenzoyl)‐7‐methoxy‐3,4‐dihydroisoquinolin‐1(2H)‐one (16u2009f) and 16u2009g and their sulfamate derivatives 17u2009f and 17u2009g (2‐(3,5‐dimethoxybenzoyl)‐7‐methoxy‐6‐sulfamoyloxy‐3,4‐dihydroisoquinolin‐1(2H)‐one and 7‐methoxy‐2‐(3,4,5‐trimethoxybenzoyl)‐6‐sulfamoyloxy‐3,4‐dihydroisoquinolin‐1(2H)‐one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A‐4, and bind competitively at the colchicine binding site of tubulin. Compounds 16u2009f and 17u2009f were also shown to demonstrate in vitro anti‐angiogenic activity. Additionally, X‐ray and computational analyses of 17u2009f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a “steroid‐like” conformation that may partially explain the excellent in vitro activities.