José Luis Vega-Baez

Diosgenin-based thio(seleno)ureas and triazolyl glycoconjugates as hybrid drugs. Antioxidant and antiproliferative profile

The stereoselective preparation of diosgenin-derived thio(seleno)ureas and glycomimetics bearing a 1,2,3-triazolyl tether on C-3 has been accomplished. The key steps in the synthetic pathway are the incorporation of an amino moiety and its further transformation into thio- and selenoureas, and also a click chemistry reaction involving a propargyl residue and an azido moiety to afford carbohydrate-derived 1,2,3-triazoles; subsequent BF3-promoted acetolysis of the spiranic moiety afforded the corresponding 22-oxocholestanic structure. The N-phenyl selenourea, an hitherto unknown steroidal derivative, turned out to be a potent ROS scavenger, in particular against free radicals (EC50 = 29.47 ± 2.33 μM, DPPH method), and as a glutathione peroxidase mimic in the elimination of H2O2 (t1/2 = 4.8 min, 1% molar ratio). 22-Oxocholestane structures bearing a C-3 azido, propargyl, thioureido, and particularly selenoureido moiety behaved as strong antiproliferative agents against HeLa cells (IC50 1.87-11.80 μM). N-phenyl selenourea also exhibited IC50 values lower than 6.50 μM for MDA-MB-231, MCF-7 and HepG2 cancer cells; apoptosis was found to be involved in its mode of action. Such compound was also capable of efficiently eliminating ROS endogenously produced by HeLa cells. Antiproliferative properties of thioxo and selenoxo derivatives were stronger than diosgenin.

Novel steroidal penta- and hexacyclic compounds derived from 12-oxospirostan sapogenins

The E ring regioselective acid-catalyzed opening of spirostanic sapogenins possessing a carbonyl group at C-12, such as botogenin and hecogenin, provided the new 12,23-cyclo-22,26-epoxycholesta-11,22-diene skeleton, in addition to new compounds of the already known 12,23-cyclocholest-12(23)-en-22-one frameworks. This transformation proceeds in a single step, under slightly acidic conditions. Both, penta- and hexacyclic steroids were obtained with retention of configuration of all asymmetric centers.

Synthesis of steroidal derivatives containing substituted, fused and spiro pyrazolines

An efficient and facile synthesis of fused, substituted and spiro pyrazoline steroid derivatives through a cycloaddition reaction of different α,β-unsaturated ketones with hydrazine acetate in acetic acid is reported. Depending on the starting material, the ring closure reaction provided a mixture of two steroidal pyrazoline epimers that were separated and studied by NMR techniques. In one case it was possible to isolate and characterize the hydrazone derivative as the reaction intermediate, which confirms the mechanism proposed in the literature [11,25,26].

Synthesis of monomeric and dimeric steroids containing [1,2,4]triazolo[1,5-a]pyrimidines

The synthesis of several monomeric and dimeric steroidal [1,2,4]triazolo[1,5-a]pyrimidines (TPs) derived from steroids are described. These derivatives were prepared from α,β-unsaturated carbonyl compounds through a Claisen Schmidt condensation and rearrangement of the spiro moiety followed by a cycloaddition with 3-amino-1,2,4-triazole. The antiproliferative activity of compounds 7, 13-15 was tested against human cancer cells; several IG50 values were below 10μM.

Rapid conversion of spirostans into furostan skeletons at room temperature

We report a facile protocol to obtain 22-substituted furostans and pseudosapogenins in high yields from (25R)- and (25S)-sapogenins. This method involves the treatment of the sapogenin with acetic-trifluoroacetic mixed anhydride and BF(3)·OEt(2) at room temperature, followed by the addition of a nucleophile (H(2)O, MeOH or KSeCN). In the case of 22-hydroxyfurostans, they can be transformed to pseudosapogenins by treatment with p-toluensulfonic acid.

Novel synthesis of steroidal oximes and lactams and their biological evaluation as antiproliferative agents

HIGHLIGHTSTwo novel and short methods to introduce the hydroxyimino group at C‐6 on the steroidal skeleton are described.An efficient route to obtain B‐homolactams in just three steps from the natural steroids is presented.The antiproliferative activity of the new steroidal oximes and lactams was evaluated. ABSTRACT A novel three‐step methodology to obtain 6a‐aza‐B‐homo steroidal lactams has been developed starting from the easily available cholesterol and pregnenolone. In addition, a new procedure for the synthesis of a 6a‐aza‐B‐homo steroidal lactam analog of vespertilin, starting from diosgenin has been established. In both synthetic pathways, the key intermediate is a hydroxyimino derivative obtained in a one‐ or two‐step sequence from the starting materials. These methods avoid the use of hazardous oxidant agents in the process. The new steroidal oximes and lactams were examined for their antiproliferative activities against several tumor cell lines. The 6,23‐dihydroxyimino derivative exhibited the highest activity with GI50 values of 11–22 &mgr;M.

Synthetic pathway to 22,23-dioxocholestanic chain derivatives and their usefulness for obtaining brassinosteroid analogues.

Recognizing the functionality of the pentacyclic steroidal derivative 7a as important synthon to obtain new brassinosteroid analogs, we have accomplished the derivatization of hecogenin, a sapogenin from the 25R serie containing a carbonyl group at C-12, to a 22,23-dioxocholestanic chain derivative. Starting from hecogenin acetate (5a) or hecogenin tosylate (5b), we obtained two pentacyclic derivatives (7a and 7b) which were subjected to an oxidation reaction on the double bond at C-12(23) to obtain a 22,23-dioxocholestanic chain, with the regeneration of the carbonyl group at C-12. Reduction of the carbonyl groups lead to the 20-epi-12,23-dihydroxy-22-oxo system 11a-b. The absolute configuration of compound 11a was established by X-ray diffraction analysis.

Accurate stereochemistry for two related 22,26-epiminocholestene derivatives.

Regioselective opening of ring E of solasodine under various conditions afforded (25R)-22,26-epiminocholesta-5,22(N)-diene-3β,16β-diyl diacetate (previously known as 3,16-diacetyl pseudosolasodine B), C31H47NO4, or (22S,25R)-16β-hydroxy-22,26-epiminocholesta-5-en-3β-yl acetate (a derivative of the naturally occurring alkaloid oblonginine), C29H47NO3. In both cases, the reactions are carried out with retention of chirality at the C16, C20 and C25 stereogenic centers, which are found to be S, S and R, respectively. Although pseudosolasodine was synthesized 50 years ago, these accurate assignments clarify some controversial points about the actual stereochemistry for these alkaloids. This is of particular importance in the case of oblonginine, since this compound is currently under consideration for the treatment of aphasia arising from apoplexy; the present study defines a diastereoisomerically pure compound for pharmacological studies.