Synthesis, structural analysis and antitumor activity of novel 17α-picolyl and 17(E)-picolinylidene A-modified androstane derivatives

Ajduković, Jovana J.; Gaši, Katarina M. Penov; Jakimov, Dimitar; Klisurić, Olivera R.; Јovanović-Šanta, Suzana; Sakač, Marija N.; Aleksić, Lidija D.; Djurendić, Evgenija A.

doi:10.1016/j.bmc.2015.02.001

Cited by 25 publications

(19 citation statements)

References 31 publications

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“…Modified androstane derivatives exhibited an antiproliferative activity against several types of human cancer cells, including breast, prostate, cervical, colon and lung adenocarcinoma [37, 61]. Here we report the parallel assessment of cytotoxicity of the compound A, an androstane derivative, delivered using submicron HAp/Ch-PLGA particles as a carrier, on two different cell lines: A549 human lung carcinoma cells and regular MRC5 human lung fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

Selective anticancer activity of hydroxyapatite/chitosan-poly(d,l)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor

Ignjatović

Penov-Gaši

et al. 2016

Colloids and Surfaces B: Biointerfaces

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In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(D,L)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. 1H NMR and 13C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the thermal degradation products and properties of A-loaded HAp/Ch-PLGA. The loading efficiency, as indicated by the comparison of enthalpies of phase transitions in pure A and A-loaded HAp/Ch-PLGA, equaled 7.47 wt.%. The release of A from HAp/Ch-PLGA was sustained, neither exhibiting a burst release nor plateauing after three weeks. Atomic force microscopy and particle size distribution analyses were used to confirm that the particles were spherical with a uniform size distribution of d50 = 168 nm. In vitro cytotoxicity testing of A-loaded HAp/Ch-PLGA using MTT and trypan blue dye exclusion assays demonstrated that the particles were cytotoxic to the A549 human lung carcinoma cell line (46±2%), while simultaneously preserving high viability (83±3%) of regular MRC5 human lung fibroblasts and causing no harm to primary mouse lung fibroblasts. In conclusion, composite A-loaded HAp/Ch-PLGA particles could be seen as promising drug delivery platforms for selective cancer therapies, targeting malignant cells for destruction, while having a significantly lesser cytotoxic effect on the healthy cells.

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Section: Resultsmentioning

confidence: 99%

Selective anticancer activity of hydroxyapatite/chitosan-poly(d,l)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor

Ignjatović

Penov-Gaši

et al. 2016

Colloids and Surfaces B: Biointerfaces

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“…The set of 17α-picolyl and 17(E)-picolinylidene androstanes has been synthesized according to the procedures described in the literature (1)(2)(3)(4)(5)(6)(7)(8). The IUPAC names of the studied eleven 17α-picolyl androstane derivatives and thirteen 17(E)-picolinylidene androstane derivatives are listed in Table 1.…”

Section: The Series Of 17α-picolyl and 17(e)-picolinylidene Androstanesmentioning

confidence: 99%

“…The idea for the synthesis of this new series of androstane derivatives has arisen from the fact that many anticancer drugs express cytotoxicity not only toward cancerous cells but also against healthy cells (1)(2)(3)(4)(5)(6)(7)(8). Therefore, the synthesis of novel compounds which will express less side effects and minimal toxicity toward healthy cells, but high toxicity toward cancer cells, is desirable.…”

Section: The Series Of 17α-picolyl and 17(e)-picolinylidene Androstanesmentioning

confidence: 99%

“…Probably, one of the most important biological activity that these compounds exhibit is antiproliferative activity toward various types of cancerous cells, including breast cancer, prostate cancer, colon cancer, lung cancer, etc. (2)(3)(4)(5)(6)(7)(8). It was determined that the introduction of heteroatom in a steroidal core will enhance the biological activity, while the heterocyclic system with a nitrogen atom has been shown to be a structural characteristic which leads to improvement of biological activity of steroidal compounds (1).…”

Section: Introductionmentioning

confidence: 99%

“…It was determined that the introduction of heteroatom in a steroidal core will enhance the biological activity, while the heterocyclic system with a nitrogen atom has been shown to be a structural characteristic which leads to improvement of biological activity of steroidal compounds (1). The group of 17α-picolyl and 17(E)-picolinylidene androstane derivatives has been synthesized and its anticancer potential has been determined (1)(2)(3)(4)(5)(6)(7)(8). It has been shown that these compounds have significant anticancer potential (1)(2)(3)(4)(5)(6)(7)(8) and they could be considered a good basis for further development of novel steroidal anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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Computational modeling of distribution coefficients and their correlations with pharmacokinetic properties of 17α-picolyl and 17(E)-picolinylidene androstane derivatives

et al. 2019

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The present study describes the computational modeling of distribution coefficient (logD) of 17α-picolyl and 17(E)-picolinylidene androstane derivatives, as a group of compounds with significant anticancer activities. The determination of logD is practically important for estimation and prediction of pharmacokinetic and pharmacodynamic behavior of compounds in a living organism and it is related to blood-brain barrier permeability, skin permeability, gastrointestinal absorption, binding to plasma proteins, etc. These features are crucial for the determination of potential drug candidates as well. The results presented in this study include determination of pH versus logD profiles, pH versus molecular charge profiles and determination of isoelectric point of eleven 17αpicolyl androstane derivatives and thirteen 17(E)-picolinylidene androstane derivatives. Since the pH of the organism differs depending on the organ (for example, the pH of the blood is significantly different from the pH of the stomach), these profiles are significant because they indicate in what form the molecule will exist and how it will be distributed between different phases at certain pH value. The influence of tautomerization and resonance was taken into account during the modeling of logD parameters. Eventually, the correlations between logD values and specific absorption, distribution, metabolism, and excretion (ADME) properties, such as human intestinal absorption (HIA) and permeability of heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2), were determined.

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Ferrocenylmethylation of estrone and estradiol: Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates

Raičević

Radulović

Jovanović

et al. 2020

Applied Organom Chemis

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Conjugates of ferrocene with steroidal estrogens as selective antiproliferative agents against hormone‐dependent breast cancer cells are believed to be limited by the inherent estrogenicity of the conjugates. Motivated by a significant cytotoxicity of the ester of ferrocenecarboxylic acid and the phenolic group of estradiol toward such a cell line, we decided to explore other a‐ring‐tethered ferrocene–estra‐1,3,5(10)‐triene conjugates; in this study, ferrocenylmethylation of estradiol and estrone with (ferrocenylmethyl)trimethylammonium iodide in the presence of potassium carbonate yielded five new compounds (1–5). In dimethylformamide, only O‐alkylated products formed (1 and 3), while a mixture of O‐ and C‐alkylated products was obtained when methanol was used (2, 4, and 5 in addition to 1 and 3). All compounds were characterized using 1D and 2D NMR, IR, UV–Vis, and high‐resolution mass spectrometry. Two of the conjugates, a 3‐O‐ and a 4‐C‐alkylated derivative of estrone (3 and 4, respectively), were also analyzed using single‐crystal X‐ray diffraction. A cyclic voltammetric investigation of the electrochemical properties of 1–5 was performed. While some of the compounds were shown to have a slight‐to‐moderate antiproliferative activity against at least one of the six tested human tumor cell lines and were nontoxic to (the noncancerous) fetal human fibroblasts, compound 2 (4‐(ferrocenylmethyl)estra‐1,3,5(10)‐triene‐3,17β‐diol) with an IC50 value of 0.34 μM was found to be more active against the hormone‐dependent breast cancer cell line MCF‐7 than doxorubicin. These results suggest that a‐ring substitution of steroidal estrogens is a plausible strategy for preparing other ferrocene–steroid conjugates acting against tumor cells.

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Synthesis, structural analysis and antitumor activity of novel 17α-picolyl and 17(E)-picolinylidene A-modified androstane derivatives

Cited by 25 publications

References 31 publications

Selective anticancer activity of hydroxyapatite/chitosan-poly(d,l)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor

Selective anticancer activity of hydroxyapatite/chitosan-poly(d,l)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor

Computational modeling of distribution coefficients and their correlations with pharmacokinetic properties of 17α-picolyl and 17(E)-picolinylidene androstane derivatives

Ferrocenylmethylation of estrone and estradiol: Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates

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