Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-connected 2-pyrazoles of estradiol and, for comparison, their structurally simplified non-steroidal pairs were synthesized from estradiol 3-methyl ether and 6-methoxy-1,2,3,4-tetrahydronaphthalene. Friedel-Crafts acetylation of the protected phenolic compounds and subsequent O-demethylation led to ortho-substituted derivatives regioselectively, which were converted to arylhydrazones with phenylhydrazine, 4-tolylhydrazine and 4-chloro-phenylhydrazine, respectively, under microwave conditions. The hydrazones were subjected to cyclization with the Vilsmeier-Haack reagent immediately after preparation and the ring closure/formylation sequence resulted in steroidal and non-steroidal 4′-formylpyrazoles in moderate to good yields. During reductive transformations, 4-hydroxymethyl-pyrazoles were obtained, while oxidative lactonization of the 4-formylpyrazole moiety with the phenolic OH in the presence of the Jones reagent afforded A-ring-integrated pyrazolocoumarin hybrids and related analogs. Steroidal pyrazoles, which were produced as C-17 acetates due to acetylation of C-17 OH during the primary Friedel-Crafts reaction, underwent deacetylation in alkaline methanol to furnish 2-heterocyclic estradiol derivatives. Pharmacological studies revealed the overall and cancer cell-specific cytotoxicity of the derivatives and the half maximal inhibitory concentrations were obtained for the most promising compounds.

Microwave-assisted syntheses of novel ring d-condensed 2-pyrazolines in the estrone series were efficiently carried out from steroidal α,β-enones and hydrazine derivatives. The ring-closure reaction of 16-benzylidene estrone 3-methyl ether with hydrazine in acetic acid resulted in a 2:1 diastereomeric mixture of two 16,17-cis fused pyrazolines, which is contrary to the former literature data for both stereoselectivity and product structure. However, the cyclization reactions of a mestranol-derived unsaturated ketone with different arylhydrazines in acidic ethanol furnished the heterocyclic products in good to excellent yields independently of the substituents present on the aromatic ring of the reagents applied. The MW conditions also permitted the ring-closure reaction with p-nitrophenylhydrazine which is unfavorable under conventional heating. Moreover, the transformations led to the heterocyclic compounds stereoselectively with a 16α,17α-cis ring junction without being susceptible to spontaneous and promoted oxidation to pyrazoles.

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<p><strong>Introduction</strong></p> <p> </p> <p>Meteorites offer large quantities of interesting and useful information regarding the formation of the Earth, the Solar System and maybe the life, but for their study, they have to be found first. This is not an easy task since these objects only glow in the upper layers of the atmosphere and after that, there is no information about their locations. Our project aims to model this phase of meteor flight, the so-called ‘dark flight’, and gather as much information about it as possible, regarding the meteors’ location, velocity, etc. </p> <p> </p> <p>In Hungary Dr Tibor Hegedüs and his high-altitude balloon team (called DAMBALL) released the task to simulate the dark flight of meteoroids by ‘artificial meteoroid’ bodies, which have their own telemetry. A part of our group (‘Soprobotics’) has developing and programming such compact data-collecting devices that can be inserted in small spheres, the falling trajectories of which would be analogous to a meteor in the phase of dark flight. These units were named Info-Droplets. When creating the droplets, the main concept was keeping them as small as possible. The desirable size were defined within the range of D=5-10 cm</p> <p> </p> <p><strong>Hardware</strong></p> <p> </p> <p><em>The Droplets’ main components</em></p> <p>Control of one device is fulfilled by a WEMOS D1 mini pro microcontroller. The most important tool of the position measurement is a GPS module, this supplies the data required by the observing team. The collected data are stored on a SD card which has its own shield. The unit is powered by a 3.7V LiPo battery.</p> <p> </p> <p><em>Evolution of the Droplets’ design</em></p> <p> </p> <p><em>Mk 1:</em></p> <p>This first device was consisted only one microcontroller, an SD-Card shield and an OCTOPART GPS which was provisionally connected with wires. This GPS works up to an altitude of 18 km due to a built-in limitation and thus it was insufficient for our purposes.</p> <p> </p> <p><em>Mk 2:</em></p> <p>The GPS was replaced by a UBLOX-NEO-M8Q which does not have the previously mentioned height limitation. This was planted on a custom PCB.</p> <p>For the additional functionality of Droplet-Droplet and Droplet-Ground communication, a LoRa RFM 95W radio module was added. This offers help in finding the droplets after the flight and supplies a log of measured data in case a unit should be lost or destroyed.</p> <p> </p> <p><em>Mk 3:</em></p> <p>Further test flights revealed potential improvements which were duly implemented. </p> <p>A new, active GPS antenna was added, the GPS shield was redesigned placing the LoRa on it as well and adding a port for the GPS antenna and a battery-control shield was added for constant supply-voltage and charging capabilities. </p> <p><img src="" alt="" /></p> <p><strong>Software</strong></p> <p> </p> <p>We programmed the microcontrollers in the Arduino IDE. For the GPS we used the TinyGPS++ library and the radio modules had their own library. This did not support the ESP based boards, but we could modify it, so the two devices could work together.</p> <p>The data collected during the fall are easily importable to Excel.</p> <p> </p> <p><em>Code structure:</em></p> <p>Upon turning on the droplet we are running the setup. Here we are starting every module (SD card, Radio, Gps). </p> <p>In the main loop we are reading the GPS and storing the data on the card. Then the communication starts via radio with the other droplets, and with the Earth unit as well.</p> <p> </p> <p><em>Setup:</em></p> <p>In the setup procedure, several fundamental things are started.</p> <p>Some basic information, we have : <br />GPS communication pins, droplet ID, droplet version, software version, etc.</p> <p>Finally, we are starting the radio and the GPS. Both modules are using SPI, we can select the one we are using through its chip selector pin.</p> <p> </p> <p><em>Main loop:</em></p> <p>Firstly, we are measuring the position of the unit by the GPS and saving it in the data variable. This includes the droplet ID, the number of satellites,  time, latitude, longitude and the altitude.</p> <p>For safety purposes we write the same data into two files simultaneously.</p> <p> </p> <p>The first part of the communication is the sending of the data variable to the other droplet and to the Earth unit. The second part is the receiving and saving the data acquired from the other droplets.</p> <p> </p> <p><em>Additional features:</em></p> <p>If the GPS loses its signal, the droplet detects this and restarts.</p> <p>We can also send some commands to the droplet via radio from the Earth unit. </p> <p>We can restart the whole device, the GPS, the radio, and get the file version and wipe the whole SD card remotely.</p> <p><img src="" alt="" /></p> <p><strong>Test flights and results</strong></p> <p>The high-altitude balloons can carry the Droplets to a height of about or more then 30 km where they blow up. The gondola, and the previously separated Droplets fall to the ground (the gondola is with a parachute and the Droplets are by a free-fall) </p> <p> </p> <p><em>August 2018: Droplets Mk 1</em></p> <p>From the data logs it was apparent that both the climb and the fall was well documented, but the part of the flight above 18000m altitude is missing owing to the GPS’s built in limitation.</p> <p> </p> <p><em>September 2019: Droplets Mk 2</em></p> <p>The first flight, where we used radio communication, but the flight data was corrupted and could not be evaluated.</p> <p> </p> <p><em>June 2020: Droplets Mk 2</em></p> <p>The horizontal part of the graph is not caused by the altitude cutoff as the UBLOX GPS was used, but the GPS modules crashed and the satellite communication was severed. Although radio communication between Droplets and the Ground unit was active, we could not solve the problem at that time.</p> <p> </p> <p>Sadly no further test flights could be conducted to date because of the COVID 19 pandemic, thus the Droplets could not be built into their spherical housings and dropped separately from the gondola to be perfect meteor-models.</p> <p><img src="" alt="" /></p> <p><em>Summary and conclusions</em></p> <p>Three successful test flights were conducted and the graphs show that our Droplets – which became quite more complex in the meantime, than our concept at the start of the project – work satisfactorily and the balloon team can use them for the original task at hand. The final test flight and the actual missions are planned for this summer.</p>

Irodalmi előzmények 2.1. Heterociklusos szteroidszármazékok a természetben 2.2. A pirazolok előállítási lehetőségei és szteránvázas képviselőik 2.3. A Mannich-reakció és lehetőségei 2.4. Egyéb stratégiák az aminocsoport szteránvázba építésére 2.5. Hibridizációra alkalmas bioaktív vegyületek (szteroidok, flavonoidok, kumarinok) 2.6. Az ösztrogének A-gyűrűjének jelentősége 3. Célkitűzés 4. Kísérleti eredmények 4.1. Pirazolil-ösztradiol származékok, pirazolokumarin-ösztradiol hibridek és analóg kismolekulák szintézise 143 4.2. Ösztradiol-flavonoid hibridek előállítása 148 4.3. 2-Aminometil-ösztron és származékainak szintézise 155 4.4. Az in vitro farmakológiai vizsgálatok eredményei 5. A felhasznált vegyszerek és módszerek általános leírása 6. Az elvégzett reakciók részletes leírása 7. Összefoglalás