Novel Coumarin-Steroid/Terpenoid Hybrids: In Vitro and In Silico Anticancer Studies.

We have synthesized a series of novel coumarin-steroid and triterpenoid hybrids and evaluated their potential anticancer activity through molecular docking calculations and in vitro antiproliferative assays. These hybrids, derived from estrone and oleanolic acid, were linked via hydrocarbon spacers of varying lengths. Molecular docking studies against human aromatase revealed strong interactions, particularly for compound 11d, which exhibited significant binding affinity (-12.

Syntheses and medicinal chemistry of spiro heterocyclic steroids.

There is compelling evidence that incorporating a heterocyclic moiety into a steroid can alter its pharmacological and pharmacokinetic properties, driving intense interest in the synthesis of such hybrids among research groups. In this review, we present an overview of recent synthetic methodologies, spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being predominant.

Synthesis, antiproliferative evaluation and in silico studies of a novel steroidal spiro morpholinone.

Estrogens play a pivotal role in the development of estrogen-dependent breast cancer and other hormone-dependent disorders. A common strategy to overcome the pathological effects of estrogens is the use of aromatase inhibitors (AIs), which bind to the enzyme and prevent the union with the natural substrate, decreasing the amount of estrogens produced. Several AIs have been developed, including inhibitors with a steroidal backbone and a nitrogen heterocycle in their structure.

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases.

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII ( within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII ( > 10 µM); CA IX was found to be slightly more sensitive towards structural changes.

Tuning the activity of iminosugars: novel -alkylated deoxynojirimycin derivatives as strong BuChE inhibitors.

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer's agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether.

Synthesis and Evaluation of Pyrimidine Steroids as Antiproliferative Agents.

A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields.

Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs.

Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines.

New selenosteroids as antiproliferative agents.

Starting from natural steroids (diosgenin, hecogenin, smilagenin, estrone), we have prepared a wide panel of selenoderivatives, including benzoselenazolones, selenosemicarbazones, isoselenocyanates, selenoureas, selenocyanates and diselenides, with the aim of developing new families of potential chemotherapeutic agents. The modification of the organoselenium moieties, and their position on the steroid provided valuable information concerning the antiproliferative activities. Among all the families accessed herein, the best profile was achieved for selenoureas on the A ring of estrone, which exhibited GI values in the range 2.

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

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.

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 IG values were below 10μM.

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.

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].

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.

Westphalen's diol diacetate: 19(10→5)-abeo-5β-cholest-9-ene-3β,6β-diyl diacetate.

THE STRUCTURE OF THE TITLE STEROID [ALTERNATIVE NAME: 3β,6β-diacet-oxy-5β-methyl-19-norcholest-9(10)-ene], C31H50O4, confirms the generally accepted mechanism for the rearrangement of a cholestan-5α-ol derivative reported a century ago by Westphalen. The methyl group at position 10 of the starting material migrates to position 5 in the steroidal nucleus, while a Δ(9) bond is formed, as indicated by the C=C bond length of 1.347 (4) Å.

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 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.

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-3beta,16beta-diyl diacetate (previously known as 3,16-diacetyl pseudosolasodine B), C(31)H(47)NO(4), or (22S,25R)-16beta-hydroxy-22,26-epiminocholesta-5-en-3beta-yl acetate (a derivative of the naturally occurring alkaloid oblonginine), C(29)H(47)NO(3). 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.