Izabella Jastrzebska

Approaches Towards the Synthesis of Cephalostatins, Ritterazines and Saponins from Ornithogalum saundersiae - New Natural Products With Cytostatic Activity

Secondary metabolites of marine invertebrates continue to attract the attention of organic chemists, biochemists, and pharmacologists due to their novel structures and potent biological activities. One such example is cephalostatin 1 isolated from the Indian Ocean hemichordate Cephalodiscus gilchristi, which exhibited remarkable cytotoxic activity against a broad spectrum of malignant tumor cells. Similar marine alkaloids (e.g. ritterazine G) were found in the lipophilic extract of the tunicate Ritterella tokioka collected off the coast of Japan. These very potent compounds, cephalostatins and ritterazines, belong to the large family of trisdecacyclic pyrazines, consisting of two steroid units. The two steroid halves of cephalostatin 1 and other highly cytotoxic members of the family are different. The biological activity of the dimeric steroid-pyrazine marine alkaloids and their limited availability coupled with the new and intriguing structure make them an attractive challenge for the synthetic organic chemists. A few years ago a group of cholestane glycosides was isolated from the bulbs of Ornithogalum saundersiae, a species of the lily family without any medicinal folkloric background. Similar glycosides were recently isolated from Galtonia candicans. The major component of the mixture of saponins, OSW-1, exhibited sub-nanomolar antineoplastic activity. While OSW-1 is exceptionally cytotoxic against various tumor cells, it showed little toxicity to normal human pulmonary cells. The cytotoxicity profile of OSW-1 against different cancer cell lines was found to be surprisingly similar to that of the cephalostatins, which appears to imply a related mechanism of action. In this review article the synthetic efforts towards these compounds are described.

Some reactions of 16α,17α-oxido-steroids: a study related to the synthesis of the potent anti-tumor Saponin OSW-1 aglycone

Abstract Five 16α,17α-oxido-steroids were subjected to acids, bases and lithium hydroperoxide. Acids caused Wagner–Meerwein-type rearrangement irrespective of the side-chain structure. The 16α,17α-epoxides proved resistant to bases unless a C(22)O group was present; in the case of 22-esters or 22-ketones the oxirane rings were cleaved with base and the corresponding allylic alcohols were formed. The reactions of 16α,17α-oxido-22-carbonyl compounds with lithium hydroperoxide resulted in the epoxide cleavage to the desired 16β,17α-diols which underwent further transformations.

Rearrangement of 23-oxospirostanes to the 22-oxo-23-spiroketal isomers promoted by Lewis acids—X-ray crystal structure of (23R,25S)-3β-acetoxy-16β,23:23,26-diepoxy-5β-cholestan-22-one

Both 25R and 25S 23-oxospirostanes undergo rearrangement to the 22-oxo-23-spiroketal isomers promoted by Lewis acids. An X-ray crystal structure analysis of the rearranged product of 23-oxosarsasapogenin acetate confirmed the R configuration at the new spiro carbon atom.

Novel transformation of 23-bromosapogenins. Synthesis of (22S,23R)-22-hydroxy-23,26-epoxyfurostanes

Abstract (22 S ,23 S )-23-Bromosapogenins undergo rearrangement to the (22 S ,23 R )-22-hydroxy-23,26-epoxyfurostanes during alkaline hydrolysis. An efficient degradation procedure of sarsapogenin via the corresponding bisfuran to the C 22 lactone is described.

Chemistry of Steroidal Sapogenins - New Advances in a Classical Field

Spirostanes, family of steroidal sapogenins continue to attract attention of organic chemists due to their easily occurring cleavage reactions in F ring and because of the renaissance of many natural structures containing steroid spiroketal moi- ety characterized by interesting biological activity. This article reviews progress in the steroid spirostanes chemistry that was published between 1992 and 2010.

Neurosteroid Analogues. 14. Alternative Ring System Scaffolds: GABA Modulatory and Anesthetic Actions of Cyclopenta(b)phenanthrenes and Cyclopenta(b)anthracenes

Although the structural features of binding sites for neuroactive steroids on gamma-aminobutryic acid type A (GABA A) receptors are still largely unknown, structure-activity studies have established a pharmacophore for potent enhancement of GABA A receptor function by neuroactive steroids. This pharmacophore emphasizes the importance of the position and stereochemistry of hydrogen-bonding groups on the steroid. However, the importance of the steroid ring system in mediating hydrophobic interactions with the GABA A receptor is unclear. We have taken the cyclopenta[ b]phenanthrene (tetracyclic compounds with a nonlinear ring system different from that of steroids) and cyclopenta[ b]anthracene (tetracyclic molecules with a linear 6-6-6-5 carbocyclic ring system) ring systems and properly substituted them to satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids. We have found these cyclopenta[ b]phenanthrene and cyclopenta[ b]anthracene analogues to have potent activity at the GABA A receptor, rivaling that of the most potent steroid modulators. Single-channel analysis of electrophysiological data indicates that similarly substituted analogues in the different ring systems affect the kinetic components of macroscopic currents in different ways. Mutations to the hydrogen bonding amino acids at the putative steroid binding site (alpha1Q241L mutation and alpha1N407A/Y410F double mutation) produce similar effects on macroscopic current amplitude by the different ring system analogues suggesting that the different kinetic effects are explained by the precise interactions of each analogue with the same binding site(s).

Photoinduced Isomerization of 23-Oxosapogenins: Conformational Analysis and Spectroscopic Characterization of 22-Isosapogenins

The first synthesis of 22-isospirostane derivatives is described. They were obtained by photochemical isomerization of 23-oxosapogenins. The structure of 23-oxo-22-isotigogenin acetate (12) was proved by a single crystal X-ray diffraction, while structures of 23-oxo-22-isodiosgenin acetate (13) and 23-oxo-22-isosarsasapogenin acetate (14) were elucidated by spectroscopic methods. 22-Isodiosgenin acetate (17) was obtained by NaBH(4) reduction of the 23-oxo derivative 13 followed by the two-step Barton-McCombie deoxygenation procedure. Conformational analysis of 22-iso compounds was carried out with CD and NMR, as well as DFT calculations.

On reactions of steroidal 23-oxo and 23,24-epoxysapogenins with Lewis acids

The reaction of 23-oxotigogenin acetate with TMSOTf in THF afforded the corresponding bisnorcholanic lactone in 60% yield. The analogous reactions carried out in dichloromethane or benzene gave the rearranged products--the isomeric spirostanic ketone (10-15%) and bisfuran (40-42%). Similar products were also obtained upon treatment of 23,24-epoxysapogenins with BF(3). The epoxides treated with TiCl(4) afforded mostly chlorohydrins and no rearranged products were detected.

Some observations on solasodine reactivity

HIGHLIGHTSThe oxidation of N,O‐diacetylsolasodine with nitrite reagents results in partial degradation of the side chain.The reaction of N,O‐diacetylsolasodine with TMSOTf leads to the corresponding pseudosapogenin.The crude pseudosapogenin readily undergoes autoxidation to pregna‐5,16‐dien‐3&bgr;‐ol‐20‐one acetate. ABSTRACT This article presents new transformations of solasodine – a representative steroid alkaloid sapogenin from the Solanum family. Oxidation of N,O‐diacetylated solasodine with either NaNO2/BF3·Et2O or t‐BuONO/BF3·Et2O resulted in partial degradation of the side chain to (20S)‐3&bgr;‐acetoxypregn‐5‐ene‐20,16&bgr;‐carbolactone (vespertilin acetate). The same starting compound when treated with TMSOTf afforded the corresponding pseudosapogenin after aqueous work‐up. However, when the crude reaction mixture was directly subjected to purification on a silica gel column, efficient autoxidation to pregna‐5,16‐dien‐3&bgr;‐ol‐20‐one acetate was observed. One‐step synthesis of this important drug intermediate from spirosolan alkaloids may be potentially exploited for large‐scale production of steroid hormones.

Erroneous epimerization at C-22 in sapogenins.

A recent report [1] about the epimerization of steroidal sapogenins at C-22 by treatment with BF3 · OEt2 is incorrect. We proved that the epimerization of sapogenins with BF3 · OEt2 occurs at C-25 as in the case of other acid-catalyzed reactions previously studied.