No description available.

No description available.

As part of our ongoing investigations for anticancer drugs from rainforestflora, five plant extracts were determined to contain interesting bioactivity. These extracts were subjected to various separation techniques, affording a number of bioactive compounds that were then characterized by spectral and degradative methods. A methanol extract of Cestrum latifolium Lam. yielded the known compound parissaponin Pb. Hydrolysis afforded its aglycone, the known spirostanol diosgenin. GCMS analysis characterized the derivatized, hydrolyzed sugars. Previous investigations of Albizia subdimidiata provided two saponins including the new compound albiziatrioside A. The sugar moieties of these two compounds required further characterization. They were characterized by spectral analysis of the partially hydrolyzed products and by GCMS analysis of the hydrolyzed sugars. Pittoviridoside, a saponin from Pittosporum viridiflorum, was isolated in a previous investigation. Further investigation was required to characterize the stereochemical environment of the sugar moiety. The stereochemistries of the pentose sugars were determined by conversion into thiazolidine acetates of known stereochemistries and analysis with standards by GCMS. Two new diterpenes were isolated from Hymenaea courbaril, which in an earlier investigation provided a new diterpene. The absolute configurations of these diterpenes were assigned on the basis of anisotropic NMR studies, X-ray crystallography, circular dichroism analysis and previously reported literature. A previous investigation of Miconia lepidota isolated two benzoquinones, primin and its n-heptyl analog. Fifteen analogs were synthesized for structure-activity relationship determination. It was found that benzoquinones with moderate-length alkyl side chains displayed the strongest activity in our yeast and cancer cell lines. / Ph. D.

Abstract available in the Journal of Oncology Pharmacy Practice.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Marie Zádrapová Supervisor: RNDr. Jana Maixnerová, Ph.D. Title of diploma thesis: Determination of renal toxicity of antineoplastics in vitro BRAF inhibitors are important antineoplastics. They work on the principle of inhibition of certain types of protein kinases and turned out to be very efficient for the treatment of melanoma. One of their disadvantages is relatively early onset of resistance; thus, it is important to look for new combinations of drugs that are already in use or work on the development of new structures with similar inhibition efficacy on melanoma cells. Encorafenib and its combination with binimetinib have been shown to be very promising drugs from the group of BRAF inhibitors, however, potential renal toxicity may be a therapeutic limitation. This thesis was focused on the determination of in vitro cytotoxicity of encorafenib on different types of renal cells in three time intervals and on its comparison with two drug standards - amphotericin B and paracetamol. Three types of morphologically and functionally different kidney cells (PODO / TERT256, HK-2 and HEK293) were used for this purpose. The cytotoxic potential was measured by colorimetric method CellTiter 96®...

O câncer é uma das principais causas de morte no Brasil e no mundo. É a segunda principal causa de morte, perdendo apenas para as doenças cardiovasculares, tornando-se um grande desafio para as autoridades de saúde pública. No Brasil, foram estimados aproximadamente 580.000 novos casos para 2014. A capacidade que alguns tumores têm de alcançarem outros órgãos faz do câncer uma doença ameaçadora, em que a metástase é responsável por 90% das mortes. A terapia antineoplásica atual baseia-se na quimioterapia, radioterapia ou remoção cirúrgica da massa tumoral. Embora eficazes em muitos casos, os fármacos antitumorais apresentam alta toxicidade, limitando seu amplo emprego. Além disso, as células tumorais podem adquirir resistência a esses compostos. Nesse cenário, as alquilfosfocolinas (APC) surgem como uma classe promissora de agentes antitumorais. O protótipo da classe das APC corresponde à miltefosina, fármaco aprovado clinicamente para o uso tópico de metástases cutâneas de câncer de mama. No entanto, este fármaco apresenta toxicidade gastrintestinal e ação hemolítica. Neste trabalho, realizamos o planejamento e a síntese de análogos alcóxicicloalquílicos da miltefosina, visando compostos com maior atividade citotóxica frente a células tumorais. A síntese foi realizada em quatro etapas, partindo-se de alcoóis previamente sintetizados a partir de dióis simétricos (10-cicloalquilmetoxi1-decanol). Estes reagiram com oxicloreto de fósforo e, subsequentemente, com a N-metiletanolamina. Por fim, uma etapa de metilação com iodeto de metila resultou nos compostos planejados. Os compostos obtidos foram o 10-cicloexilmetoxi decilfosfocolina e o 10-ciclobutilmetoxi decilfosfocolina que resultaram em um rendimento global de 37% e 29%, respectivamente, e pureza cromatográfica de 98% e 96%, respectivamente. No ensaio de viabilidade celular os compostos obtidos demonstraram menor atividade citotóxica que a miltefosina nas concentrações de 40 µM, 50 µM e 60 µM frente às linhagens celulares H358 e A549. Entretanto, em ensaio de colônia os compostos apresentaram aproximadamente 50% de inibição das células Hela, nas concentrações de 30 µM, 60 µM e 100 µM. Assim é importante que a atividade dos compostos seja investigada frente a outras linhagens celulares tumorais, visto que apresentaram efeitos antiproliferativos, sendo potencialmente promissoras como quimioterápicos. / Cancer is a leading cause of death worldwide. It configures alone second leading cause of death, displaced only by cardiovascular disease, a major challenge for public health authorities. In Brazil, around 580,000 new cases are estimated in 2014. The ability of some tumors to reach other organs makes cancer a threatening condition as metastasis is responsible for 90 % of deaths. The antineoplastic therapy is based on the current chemotherapy, radiation therapy or surgical removal of the tumor mass. While effective in many cases, antitumor drugs have high toxicity, what limits their widespread use. Furthermore, tumor cells may acquire resistance to these compounds. In this scenario, the alkylphosphocoline (APC) arise as a promising class of antitumor agents. The prototype of APC class is miltefosine, a clinically approved drug for topical cutaneous metastases of breast cancer. However, this drug shows gastrointestinal toxicity and hemolytic activity. In this work, design and synthesis of alcoxycycloalkyl analogs of miltefosine, targeting compounds with increased cytotoxic activity against tumor cells. The synthesis was carried out in four stages, starting with alcohols previously synthesized from symmetrical diols (10-cycloalkylmethoxy1-decanol). These reacted with phosphorus oxychloride and subsequently with N-methylethanolamine. Finally, a step methylation with methyl iodide resulted in the planned compounds. The analogous compounds that have been proposed are 10-cycloexylmethoxy decylphosphocholine and 10-cyclobutylmethoxy decylphosphocholine, which were obtained with a overall yield of 37% and 29% and had a chromatographic purity of 98% and 96% respectively. Nevertheless, the compounds showed lower cytotoxicity than miltefosine at 40 mM, 50 mM and 60 mM, in the cell viability assay employing A549 and H358 cell lines. However, in the colony assay the compounds showed approximately 50% inhibition of Hela cells at concentrations of 30 µM, 60 µM and 100 µM. Therefore, further biological tests should be performed ir order to better investigate the potential of these compounds as novel chemotherapeutic agents.

Excerpt: Interactions between chemotherapy and dietary or herbal supplements can compromise patient care.

Purpose: Drug interactions are a concern in oncology with the shift toward oral antineoplastics (OAs). Using electronic databases to screen for drug interactions with OAs is a common practice. There is little literature to guide clinicians on the reliability of these systems with OAs. The primary objective of this study was to explore the sensitivity of commonly available drug interaction databases in detecting drug interactions with OAs. Methods: A list of 20 drug interactions with OAs was developed by two Board-certified oncology pharmacists. The list included multiple types of drug interactions. The sensitivity in detecting these interactions by MicroMedex, Facts & Comparisons, Lexi-Interact, and Epocrates were evaluated. These databases were chosen based on their local availability and widespread use in practice. Drugs.com was evaluated as a surrogate for a patient-accessible drug interaction database. The Cochran Q test was used to assess the sensitivity distribution across the five groups. Results: Lexi-Interact and Drugs.com had a sensitivity of 95% for the 20 tested drug interaction pairs. Epocrates had a sensitivity of 90%, and both Micromedex and Facts & Comparisons had a sensitivity of 70%. There was a statistically significant difference (P = .016) in the distribution across the databases in detecting clinically significant drug interactions. Conclusion: Commonly used databases for identifying drug interactions with oral antineoplastics vary significantly in their sensitivity. Clinicians should not rely on a single database and should consider using multiple resources as well as sound clinical judgment. Further work is needed in this area.

O câncer é uma das principais causas de morte no Brasil e no mundo. É a segunda principal causa de morte, perdendo apenas para as doenças cardiovasculares, tornando-se um grande desafio para as autoridades de saúde pública. No Brasil, foram estimados aproximadamente 580.000 novos casos para 2014. A capacidade que alguns tumores têm de alcançarem outros órgãos faz do câncer uma doença ameaçadora, em que a metástase é responsável por 90% das mortes. A terapia antineoplásica atual baseia-se na quimioterapia, radioterapia ou remoção cirúrgica da massa tumoral. Embora eficazes em muitos casos, os fármacos antitumorais apresentam alta toxicidade, limitando seu amplo emprego. Além disso, as células tumorais podem adquirir resistência a esses compostos. Nesse cenário, as alquilfosfocolinas (APC) surgem como uma classe promissora de agentes antitumorais. O protótipo da classe das APC corresponde à miltefosina, fármaco aprovado clinicamente para o uso tópico de metástases cutâneas de câncer de mama. No entanto, este fármaco apresenta toxicidade gastrintestinal e ação hemolítica. Neste trabalho, realizamos o planejamento e a síntese de análogos alcóxicicloalquílicos da miltefosina, visando compostos com maior atividade citotóxica frente a células tumorais. A síntese foi realizada em quatro etapas, partindo-se de alcoóis previamente sintetizados a partir de dióis simétricos (10-cicloalquilmetoxi1-decanol). Estes reagiram com oxicloreto de fósforo e, subsequentemente, com a N-metiletanolamina. Por fim, uma etapa de metilação com iodeto de metila resultou nos compostos planejados. Os compostos obtidos foram o 10-cicloexilmetoxi decilfosfocolina e o 10-ciclobutilmetoxi decilfosfocolina que resultaram em um rendimento global de 37% e 29%, respectivamente, e pureza cromatográfica de 98% e 96%, respectivamente. No ensaio de viabilidade celular os compostos obtidos demonstraram menor atividade citotóxica que a miltefosina nas concentrações de 40 µM, 50 µM e 60 µM frente às linhagens celulares H358 e A549. Entretanto, em ensaio de colônia os compostos apresentaram aproximadamente 50% de inibição das células Hela, nas concentrações de 30 µM, 60 µM e 100 µM. Assim é importante que a atividade dos compostos seja investigada frente a outras linhagens celulares tumorais, visto que apresentaram efeitos antiproliferativos, sendo potencialmente promissoras como quimioterápicos. / Cancer is a leading cause of death worldwide. It configures alone second leading cause of death, displaced only by cardiovascular disease, a major challenge for public health authorities. In Brazil, around 580,000 new cases are estimated in 2014. The ability of some tumors to reach other organs makes cancer a threatening condition as metastasis is responsible for 90 % of deaths. The antineoplastic therapy is based on the current chemotherapy, radiation therapy or surgical removal of the tumor mass. While effective in many cases, antitumor drugs have high toxicity, what limits their widespread use. Furthermore, tumor cells may acquire resistance to these compounds. In this scenario, the alkylphosphocoline (APC) arise as a promising class of antitumor agents. The prototype of APC class is miltefosine, a clinically approved drug for topical cutaneous metastases of breast cancer. However, this drug shows gastrointestinal toxicity and hemolytic activity. In this work, design and synthesis of alcoxycycloalkyl analogs of miltefosine, targeting compounds with increased cytotoxic activity against tumor cells. The synthesis was carried out in four stages, starting with alcohols previously synthesized from symmetrical diols (10-cycloalkylmethoxy1-decanol). These reacted with phosphorus oxychloride and subsequently with N-methylethanolamine. Finally, a step methylation with methyl iodide resulted in the planned compounds. The analogous compounds that have been proposed are 10-cycloexylmethoxy decylphosphocholine and 10-cyclobutylmethoxy decylphosphocholine, which were obtained with a overall yield of 37% and 29% and had a chromatographic purity of 98% and 96% respectively. Nevertheless, the compounds showed lower cytotoxicity than miltefosine at 40 mM, 50 mM and 60 mM, in the cell viability assay employing A549 and H358 cell lines. However, in the colony assay the compounds showed approximately 50% inhibition of Hela cells at concentrations of 30 µM, 60 µM and 100 µM. Therefore, further biological tests should be performed ir order to better investigate the potential of these compounds as novel chemotherapeutic agents.

<p>U radu je predstavljena sinteza i karakterizacija&nbsp; novog fulerenol/doksorubicin nanokompozita, sintetisanog sa ciljem dobijanja potencijalne nove nanoformulacije postojećeg antineoplastika doksorubicina, koja bi pokazala veću biolo&scaron;ku aktivnost uz smanjenje neželjenih sporednih efekata koje sam lek izaziva, na prvom mestu kardiotoksičnosti.</p><p>Nanokompozit fulerenol/doksorbicin je okarakterisan brojnim&nbsp; metodama prateći dva osnovna eksperimentalna pristupa: molekulsko-spektroskopske metode (XPS, denzitometrija i transportne osobine, NMR, UPLC, Ramanska i UV-spektroskopija, SFM) i metode&nbsp; nanokarakterizacije (DLS, AFM, TEM), kao i računske simulacije(RDF). Osnovni cilj ispitivanja je bila detekcija postojanja&nbsp;nekovalentnog nanokompozita koji ostvaruju doksorubicin i fulerenolske nanočestice u vodenom rastvoru. Rezultati karakterizacije jasno i nedvosmisleno ukazuju na postojanje nekovalentnih interakcija unutar nanokompozita, &scaron;to dalje utiče na organizaciju i udruživanje čestica, a &scaron;to uslovljava i drugačiju biolo&scaron;ku aktivnost takvog sistema u odnosu na pojedinačne komponente.&nbsp; Rezultati biolo&scaron;kih ispitivanja na&nbsp;<em>in vitro</em>&nbsp;modelu različitih tumorskih ćelijskih linija pokazuju&nbsp; značajan&nbsp;antiproliferativni efekat nanokompozita, kao i selektivnost prema tumorskim u odnosu na zdravu ćelijsku liniju. Eksperimenti na <em>in vivo</em> modelu zebrica potvrđuju smanjenje toksičnosti nanokompozita u poređenju sa lekom, primarno kardiotoksičnosti. Računske simulacije, mikroskopski i spektroskopski podaci, kao i rezultati&nbsp; <em>in vitro</em> i <em>in vivo</em> studija ukazuju na to da nekovalentne interakcije između fulerenola i doksorubicina mogu biti ključni korak u stvaranju sinergističkog sistema za dostavu leka u biolo&scaron;ki sistem.</p><p>Multipotentnost fulerenola kao nanonosača lekova i nespecifičnost strukture doksorubicina kao leka, ukazuje na to da bi fulerenol mogao biti efikasan nanonosač i drugih antineoplastika, &scaron;to daje prostora za unapređenje antitumorskih osobina lekova posredstvom istovremene administracije leka.</p> / <p>The focus of this thesis was the synthesis and characterization of a novel fullerenol/doxorubicin nanocomposite, with the aim to obtain a potential nanoformulation of antineoplastic drug doxorubicin, which would&nbsp; express greater biological activity and lower level of adverse effects than the drug itself, in the first place cardiotoxicity.</p><p>Nanocomposite fullerenol/doxorubicin was characterized by means of numerous methods&nbsp; following two main experimental approaches: molecular-spectroscopic methods (XPS, densitometry and transport properties, NMR, UPLC, Raman and UVspectroscopy, SFM) and mehods of&nbsp; anocharacterisation&nbsp; (DLS, AFM,&nbsp; TEM), as well as computer simulations (RDF). The goal of characterization was detection of&nbsp; non-covalent interactions within nanocomposite that are established between fullerenol nanoparticles and doxorubicin in aqueous solution. The results clearly indicate the existence of non- covalent interactions within nanocomposite that affect the organization and assembling of the particles, which further exhibit different biological activity of such a system in comparison to components themselves. Results of biological activity on <em>in vitro </em>model of different tumor cell lines show significant antiproliferative effect of&nbsp; nanocomposite, as well as selectivity towards tumor cell lines. Experiments conducted on <em>in vivo</em> zebrafish model confirm the lowering ofthe adverse effects of the drug, especially cardiotoxicity, in case when nanocomposite was applied. Computer simulations, microscopic and&nbsp; spectroscopic results combined with encouraging <em>in vitro </em>and <em>in vivo</em> results point out&nbsp; that non-covalent interactions between fullerenol nanoparticles and doxorubicin may present the keyrole in formation of a synergistic system for nanodrug delivery into biological system. Multipotential of fullerenol nanoparticles as a nanocarrier and non-specific structure of doxorubicin as a drug imply that fullerenol may serve as a efficient nanocarrier of numerous other antineoplastics, which further allows the improvement of antitumor properties of drugs withsimultaneous drug administration.</p>