Alexandros Strongilos

A New Efficient Route for Multigram Asymmetric Synthesis of Alkannin and Shikonin

A short and convergent approach for the synthesis of alkannin, shikonin and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with enone 7 affords the complete aromatic system in just one step with concomitant attachment of the entire side chain. Subsequent Coreys oxazaborolidine mediated asymmetric reduction of the above advanced intermediate, leads to the required isomer in high enantiomeric excess. Finally, a selective and high yielding deprotection protocol furnishes the title compounds as pure crystalline precipitates. Thus, a multigram synthesis of shikonin, alkannin and shikalkin is achieved in high yield and enantioselectivity.

Asymmetric synthesis of alkannin and shikonin

Abstract A new general and convergent route for the synthesis of the title compounds is presented. The polyoxygenated aromatic ring system is annulated in one operation by the condensation of a Michael type acceptor with an 1,4 dipole equivalent. The chiral center of the target is introduced via an asymmetric allyl boration in high ee. Overall, the fully protected natural product is constructed within 8 steps in 35% total yield.

Regioselective oxidation of 3-monosubstituted juglone derivatives

Abstract Derivatives of 3-substituted juglones with either electron-withdrawing or -donating substituents are regioselectively oxidized to o - or p -naphthoquinones using salcomine/air or [bis(trifluoroacetoxy)iodo]benzene, respectively. The structure of the oxidation products was confirmed by chemical transformations. A correlation between chemical shift of the single quinoid proton and the quinone structure was established.

Rationally Designed Less Toxic SPD‐304 Analogs and Preliminary Evaluation of Their TNF Inhibitory Effects

SPD‐304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD‐304 contains a potentially toxic 3‐alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD‐304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron‐withdrawing substituents at the indole moiety, in conjunction with elimination of the 6′‐methyl group of the 4‐chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.

Synthesis of Hydroxylated Naphthoquinone Derivatives

The use of the Stobbe condensation for the synthesis of juglone derivatives is presented, together with studies towards their further functionalization. The regiospecific oxidation of the above products to o- or p-naphthoquinones was also investigated. Finally, the preparation of useful intermediates for the synthesis of related natural products such as alkannin and shikonin is proposed. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis and biological evaluation of potential small moleculeinhibitors of tumor necrosis factor

Inhibition of tumor necrosis factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of rheumatoid arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNFinhibitors. Our results show that small structural changes produce ligands with similar binding affinities (Kd) for TNF, but significantly different potencies in a L929 cell-based assay. In addition, contrary to the high affinity of compounds 4e, 8c and 10e for TNF in vitro, the potency of these compounds was determined to be low. We propose that these differences can partly be explained by the physicochemical characteristics of the synthesized SPD-304 analogs. Our findings were supplemented by molecular docking studies on the TNF dimer. These synthesized analogs may serve as a starting point for developing novel TNF inhibitors.

Cover Picture: Chem. Eur. J. 8/2002

The cover picture shows a schematic representation of the parallel history of alkannin and shikonin. Dioscorides, the founder of pharmacognosy, in his work “De Materia Medica”, around 77 AD (book shown under the magnifying lens), described the therapeutic properties of the roots of the plant Anchusa tinctoria (also known as Alkanna tinctoria). Concurrently, at the other half of the northern hemisphere, in China, the extracts from the roots of the plant Lithospermum erythrorhizon were used for silk dyeing and as crude anti-inflammatory drugs by the famous surgeon Hua To. At the beginning of 20th century, Japanese chemists Majima and Kuroda isolated a red pigment from Lithospermum erythrorhizon, which later proved to be shikonin (structure shown in the picture). In 1936, Brockmann “connected” the two stories by elucidating the structure of the red component of Anchusa tinctoria to be the optical antipode of shikonin, namely alkannin (shown in the mirror). Since then, many articles regarding the chemistry, biology, and pharmacological profile of alkannin, shikonin, the racemic mixture (shikalkin), and their derivatives have been reported. Today, the title compounds and their analogues constitute the major active ingredients of several commercially available ointments, such as HELIXDERM and Koushikon. An efficient and scalable synthesis of these molecules is presented by E. A. Couladouros et al. on p. 1795 ff.