Jorge A. R. Salvador

Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity

A series of new imidazole carboxylic esters (carbamates) and N-acylimidazole derivatives of betulin and betulinic acid (14-29) have been synthesized. The new compounds were screened for in vitro cytotoxicity activity against human cancer cell lines HepG2, Jurkat and HeLa. A number of compounds have shown IC(50) values lower than 2 microM against the cancer cell lines tested and the vast majority has shown a better cytotoxicity profile than betulinic acid, including the betulin derivatives. N-Acylimidazole derivatives 26 and 27 (IC(50) 0.8 and 1.7 microM in HepG2 cells) and the C-3 carbamate derivative 16 (IC(50) 2.0 microM in HepG2 cells) were the most promising compounds. Based on the observed cytotoxicity, structure-activity relationships have been established.

Copper-catalysed allylic oxidation of Δ5-steroids by t-butyl hydroperoxide

Abstract Δ 5 -7-Oxosteroids are efficiently prepared from Δ 5 -steroids with t -BuOOH and a copper catalyst, either Cu(II) and Cu (I) salts or Cu metal; selectivity in the presence of a secondary alcohol is observed.

Ursane-type pentacyclic triterpenoids as useful platforms in anticancer drug discovery

This review highlights the potential of natural and semisynthetic ursane-type triterpenoids as candidates for the design of multi-target bioactive compounds, with focus on their anticancer effects. A brief illustration of the biosynthesis, sources, and general biological effects of the main classes of naturally occurring pentacyclic triterpenoids (PTs) are provided.

Synthesis and structure–activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid

Chemical transformation studies were conducted on betulin and betulinic acid, common plant-derived lupane-type triterpenes. The concise synthesis, via a stepwise approach, of betulin and betulinic acid carbamate and N-acylheterocyclic containing derivatives is described. All new compounds, as well as betulinic acid were tested in vitro for their cytotoxic activity. Most of the compounds have shown a better cytotoxic profile than betulinic acid, including the synthesized betulin derivatives. Compounds 25 and 32 were the most promising derivatives, being up to 12-fold more potent than betulinic acid against human PC-3 cell lines (IC(50) values of 1.1 and 1.8 microM, respectively).

Synthesis and evaluation of novel 17-indazole androstene derivatives designed as CYP17 inhibitors

A series of novel 1H- and 2H-indazole derivatives of the commercially available dehydroepiandrosterone acetate have been synthesized and tested for inhibition of human cytochrome 17alpha-hydroxylase-C(17,20)-lyase (CYP17), androgen receptor (AR) binding affinity, and cytotoxic potential against three prostate cancer (PC) cell lines.

Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells

A series of new heterocyclic derivatives of ursolic acid 1 were synthesized and evaluated for their antiproliferative activity against AsPC-1 pancreatic cancer cells. Compounds 24-32, with an α,β unsaturated ketone in conjugation with an heterocyclic ring in ring A have improved antiproliferative activities. Compound 32 is the most active compound with an IC(50) of 1.9 μM which is sevenfold more active than ursolic acid 1. Compound 32 arrests cell cycle in G1 phase and induces apoptosis in AsPC-1 cells with upregulation of p53, p21(waf1) and NOXA protein levels.

New betulinic acid derivatives induce potent and selective antiproliferative activity through cell cycle arrest at the S phase and caspase dependent apoptosis in human cancer cells.

New semisynthetic derivatives of betulinic acid (BA) RS01, RS02 and RS03 with 18-45 times improved cytotoxic activity against HepG2 cells, were tested for their ability to induce apoptosis and cell cycle arrest in HepG2, HeLa and Jurkat cells. All the compounds induced significant increase in the population at the S phase more effectively than BA. RS01, RS02 and RS03 were also found to be potent inducers of apoptosis with RS01 being markedly more potent than BA, suggesting that the introduction of the imidazolyl moiety is crucial for enhancing the induction of apoptosis and the cell cycle arrest. The mechanism of apoptosis induction has been studied in HepG2 cells and found to be mediated by activation of the postmitochondrial caspases-9 and -3 cascade and possibly by mitochondrial amplification loop involving caspase-8. These facts were corroborated by detection of mitochondrial cytochrome c release and DNA fragmentation. Because RS01, RS02 and RS03 exhibited significant improved antitumor activity with respect to BA, they may be promising new agents for the treatment of cancer. In particular, RS01 is the most promising compound with an IC(50) value 45 times lower than BA on HepG2 cells and 61 times lower than the one found for the non-tumoral Chang liver cells.

Catalytic Oxidative Processes in Steroid Chemistry: Allylic Oxidation, β-Selective Epoxidation, Alcohol Oxidation and Remote Functionalization Reactions

The preparation of steroids containing oxygenated functions in suitable positions of the steroid nucleus is of great importance and can be achieved by means of several oxidative processes. In this paper allylic oxidation,  -selective epoxidation, alcohol oxidation and remote functionalization reactions in steroid substrates are reviewed. Focus has been given to catalytic processes because of their major importance from the viewpoint of synthetic organic chemistry. Steroid compounds are widely distributed in nature. The living organism, both animal and vegetable, contains steroids which play an important role in its vital activity. Over the last decades, hundreds of steroid compounds have been isolated from natural sources and many thousands of them have been obtained synthetically. Moreover, steroids are challenging substrates for the synthesis of a wide variety of important biologically active molecules. The preparation of steroids containing oxygenated functions in the steroid nucleus is of major importance and can be performed by means of several oxidative processes. Among the available methods, allylic oxidation,  -selective epoxidation, alcohol oxidation and remote functionalization reactions were chosen to discuss in this review. Special emphasis has been given to the allylic oxidation of steroidal alkenes to the corresponding enones. The  5 -7-keto deri- vatives are of great importance due to their relevant bio- logical properties.  -Selective epoxidation has been consi- dered because the  -epoxides are normally difficult to obtain in organic synthesis. Moreover, this functionality has been found in a number of biologically active steroids, parti- cularly the 5 ,6 -epoxides. The oxidation of steroidal satu- rated, allylic and homoallylic alcohols is also reviewed. Of particular relevance is the synthesis of  4 -3-ketones, a typical functionality of the major class of steroidal hor- mones. Finally, remote functionalization in steroid substrates has been considered. Its practical goal lies in the possibility of obtaining bioactive compounds from readily available sterols or bile acid sources, through regio- and stereo- selective remote oxyfunctionalization of unactivated carbons, avoiding multistep syntheses. Environmentally benign and sustainable transformations are now considered to be basic goals and requirements in the development of modern organic synthesis. There has been a growing effort in the replacement of stoichiometric pro- cedures, using classical toxic waste-producing oxidants, with

Oxidations with potassium permanganate — metal sulphates and nitrates. β-Selective epoxidation of Δ5-unsaturated steroids

Abstract The β-epoxidation of 3 β -acetoxy-Δ 5 -unsaturated steroids has been achieved with mmerous potassium permanganate-metal sulphates and nitrates with a high degree of stereoselectivity. 5β,6β-Epoxides are formed in a one step reaction in good yields and using very low cost reagents. The best results were achieved with KMnO 4 /Fe 2 (SO 4 ) 3 .nH 2 O.

Bismuth compounds in medicinal chemistry

In recent years, the chemical potential of bismuth and bismuth compounds has been actively exploited. Bismuth salts are known for their low toxicity, making them potential valuable reagents for large-scale synthesis, which becomes more obvious when dealing with products such as active pharmaceutical ingredients or synthetic intermediates. Conversely, bismuth compounds have been widely used in medicine. After extensive use in the treatments of syphilis and other bacterial infections before the advent of modern antibiotics, bismuth compounds remain important for the treatment of several gastrointestinal disorders and also exhibit antimicrobial properties and cytotoxic activity, among others. This review updates relevant advances in the past few years, concerning the application of bismuth reagents and catalysts in innovative synthetic processes for the preparation of compounds of medicinal interest, as well as the preparation, biological evaluation and potential medicinal uses of bismuth compounds.