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As yperit started to treat cancer (more or less) / SurprizingFacts

Recently, I accidentally got into a conversation with a person with leukemia in a clinic, and this led me to write a little about some of the first, and still major, chemotherapeutic drugs Cancer treatment. And most importantly – how they were created.

But first a little bit about yapritah. Istreet is far from alone, there are several of them and I will tell about all of them.
The first mustard, first used by the Germans, and then by the Allies in the First World War, 2,2'-dichlorodiethylsulfide, had the formula -S (C2H4Cl) 2 or
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Means that they are simply "poured" the enemy with shelling, in fact, each OB has its own tactical niche, often very narrow. Tactical niche of mustard is to make some terrain inaccessible or at least inaccessible for a relatively long period. Yperite is extremely toxic, even a small drop of it remaining on the clothes will disable not only the owner of clothes, but also anyone who will be with him in the same room. At the same time, its degassing is very laborious – the mustard is dissolved and absorbed into almost all materials – from bricks to rubber. In particular, this is due to the two-hour norm of being in one gas mask in the area contaminated with mustard gas. However, even in ideal conditions to supply mustard gas is not so simple – it interacts rather slowly with solutions of bleach, its degassing requires mixing. It is an oil-like substance. As an example, I quote memories of a certain NM Gogello from the book of L. Fedorov (the main man in Russia on the problems of chemical weapons):
"My father, an artilleryman by training, served as the head of the art warehouse in Odessa after the revolution, and in 1923 was seconded to Moscow, where he was assigned to serve in the chemical test site in Kuzminki. Soon the father received ispritnoe defeat: at the opening of the projectile drop fell on the boot, he did not notice, and did not know, probably, what it is. Three months he sat on the veranda (it was summer) with an elongated leg, on the rise of which was a terrible ulcer. I heard scraps of conversation with colleagues who visited him and discussed the insidious properties of mustard gas. Later, my father told me that it was his and his colleagues' job to deal with the captured shells – their design and what they stuffed. In parallel with the service in the chemical field, the pope studied at the chemical faculty of the Moscow Higher Technical School (in those years there was a chemical faculty).
Of course, mustard was not used in its pure form, and it would be strange to expect an inscription on the "Yprit" shell. According to the German nomenclature of times, the 1 st world mustard was the main component of the chemical shells "yellow cross" filled with a mixture of
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At the same time, any sharply smelling waste from organic synthesis enterprises was added to the mixtures – on the one hand, the "unknown" OM significantly reduced the fighting spirit of the enemy soldiers, on the other, made it difficult to analyze the mixture.
Because of the properties of yperite, the effectiveness of its use was very high-shells with it were of course attacked not by the enemy positions that had to be occupied by their troops, but those from which the enemy had to be fired. Or, to infect with a mustard portion of the terrain so that the enemy can not cross it. In a tactical sense, this is an exceptional opportunity. Let us recall the Soviet watering machines of the interwar era, which were designed on the basis of German equipment for infecting the territory of the OM. Equipment, as well as a certain part of the technology for the production of OM, were transferred to the USSR by the Weimar Republic in the late 1920s.
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Yperite is very, very toxic. Although the data on its LD are different and may seem relatively low, for OV the main is the practical result of the application, which is often radically different from the LD index. For example, the strongest poison is botulism toxin with LD50 according to the current data of 1.3-2.1 * 10-9 g / kg. In VX LD50, only 70 * 10-6 g / kg i.e. The difference would seem to be more than four orders of magnitude. On the same experiment, it turned out that when the terrain is infected, the toxin of botulism is inferior in effectiveness to VX. Therefore, it can be concluded that mustard used the title of "king of poisons" in the 1920s with good reason. For mustard gas, the main property is a bright cytotoxic effect – the ability to cause death of body cells with which it comes into contact. The presence of mustard on the skin causes severe necrosis, in the area of ​​the joints – lesions that result in joint loss of mobility, in the eyes – blindness, oral mustache intake – generally speaking, death, etc. The modern view of the mechanism of the action of mustard gas is reduced to the fact that it alkylates DNA, damaging it, as a result of which a self-destruct mechanism is included in the cell. Very schematically, the reaction looks like this:
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As can be seen, the mustard molecule is isomerized into a cation which is a Lewis acid, therefore, there is nothing unusual in its reaction with the Lewis base-amino group in DNA-no
Wikipedia says that the mustard is an alkylating agent, which from a chemical point of view is not entirely true. The fact is that under normal chemical reactions of its alkylating action it almost does not show – with ammonia reacts only when heated in a sealed ampoule, with amines – in the presence of a weak base, with amino acids (which are the basis of proteins) interacts very poorly. More or less active reactions only with secondary amines. So it can be said that here with mustard gas it is "lucky" – it is active enough to damage DNA, but it is not too active to lose the opportunity to get into the cell itself, subjected to hydrolysis, plus its convenient physical properties (high-boiling liquid). Because of this, the efforts of chemists in many countries in the interwar period were devoted to the synthesis of mustard gas, the search for its more toxic analogs and the improvement of operational properties. It was in the sense of the virulence of scientists that an unpleasant surprise awaited – many substances with mustard-like cytotoxic properties were found, but the mustard itself was almost an exceptional poison. Really adopted weapons were only so-called. Oxygen mustard and nitrogen mustard
Oxygen mustard with the formula
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Were obtained immediately in a mixture with conventional mustard action of concentrated hydrochloric acid on thiodiglycol at elevated temperature (UK). Nothing noticeable in history, he did not excel.
What can not be said about nitrogen mustard, the development of which was most actively conducted in the US (although in Germany at the end of the war, it was found about 2 thousand tons of nitrogen mustard, which by the standards of OV – not very much). We recall the formula of mustard gas in the beginning. And here is a tris (2-chloroethyl) amine quite similar to it, although it was studied in detail only in the mid-1930s
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The action of this substance turned out to be very similar to the action of mustard gas, moreover, it even had certain advantages in front of it. In particular, it was much more resistant to oxidation, therefore, it was more difficult to degas it than mustard gas. Industrial synthesis was carried out by chlorination of triethanolamine
N (C2H4OH) 3 + 3SOCl2 = N (C2H4Cl) 3 + 3SO2 + 3HCl
If someone noticed, then triethanolamine is a part of many fluxes for soldering, for example LTI-120. As far as I know, although triethanolamine is included in the list of precursors for the production of OM, anyone can buy it. Like thiodiglycol, by the way, the main raw material for obtaining conventional mustard gas. Speaking about triethanolamine, you can notice that by its poisonous nature it is certainly very, very far from nitrogenous mustard, however, it can not be called absolutely harmless and it requires caution in circulation.
Returning to nitrogen mustard – studies then showed that the most important is the presence of two groups -CH2CH2Cl at one nitrogen atom, the third group can be different. Therefore, two more nitrogenous mustard bis (2-chloroethyl) ethylamine were adopted
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And bis (2-chloroethyl) methylamine
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In parallel to the work on the study of chloroethanolamines as OB, at Yale University (USA) studies on their medical use were conducted. In those days, radiotherapy was also just beginning, it is clear that it is not difficult to draw a parallel between the effect of ionizing radiation on the body and the effect of mustard gas. In both cases the symptoms are somewhat similar. This, probably, prompted A. Gilman and L. Goodman to think about trying to treat cancer with the help of mustard gas. The first drugs that they used in the early 1940s were exactly three nitrogen mustards, probably the first drug was bis (2-chloroethyl) methylamine under the names chloromethine, mechlorethamine, later in the USSR embichine. Although this substance is still used in medicine, one should not expect that a miracle happened – initially the tumors left, but then returned again, with a loss of sensitivity to chloromethine. However, this drug still later found its niche in the field of leukemia treatment. Even a not quite positive result was a breakthrough at that time, a somewhat late publication caused a wave of research in the field of chemotherapeutic antitumor drugs, especially derivatives of nitrogenous mustard gas. As a result, a huge amount of drugs with all the same grouping-N (C2H4Cl) 2 or = N (C2H4Cl) that had a more significant effect on the tumor and a slightly less destructive effect on the body was synthesized. Nevertheless, the dangerous properties of nitrogenous mustard drugs were preserved.
Interestingly, all mustard gas is a carcinogen – due to damage to the DNA of healthy cells, they are really capable of provoking cancer. Yperits are included in the 1st group of carcinogens from IARC, i.e. A group of substances whose carcinogenic effects on humans have been proven. In the same list is found and tamoxifen – a widely used remedy against breast cancer. How does it happen that drugs that treat cancer themselves cause it? It's just an apparent paradox, it's absolutely logical – if the substance causes the death of ordinary cells, then it will surely cause the death of cancer cells, the more they are more "tender." One day I happened to get an English-language video in questions and answers format about cancer (or just tumors), which probably would not have been remembered to me, if there were no question like "Why not take cancer cures by analogy with vitamins to avoid it ? "LOL. Now the reader is clear that the use of such drugs on a healthy person will at least worsen his health, can cause cancer, and an overdose will simply kill how mustard is killed.
Well, for the sake of interest, I quote the formulas of chemotherapeutic antitumor drugs in which the reader will easily find the basis of an osmotic mustard:
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Uramustine, chloroethylaminouracil, uracil mustard, dopane
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Melphalan "Alkeran", "Sarkolizin"
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Chlorambucil
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Bendamustine
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Mannomustine, Degranol
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Prednimustine
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Estramustine
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Novembikhin
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Pafenzil
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Lofenal
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Cyclophosphamide
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Ifosfamide
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Mafosfamide
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Trofosfamide, Iksoten
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Perfosfamide, Pergamid
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Hydroxycyclophosphamide
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Aldophosphamide
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Glyfosfamide
In conclusion

Summing up what has been said, one can ask how many people died as a result of the use of mustard gas (on the spot, from the consequences, in the production of mustard gas, in the process of its utilization, etc.) and how many received Additional years, sometimes even decades, as a result of the use of chemotherapy drugs based on mustard gas? Personally, I'm sure that the number of the second already long ago exceeded the number of the first, so in this case the proverb "no good without good" works. For example, if there were no application of skin-tearing agents during the First World War, the use of antitumor drugs would be delayed for several decades, perhaps even for a longer period. It also happened with the chemistry of arsenic – the search for new OBs based on arsenic gave a powerful impetus to the chemotherapeutic drugs of syphilis (however, the chemistry of arsenic compounds developed during the pre-war period).

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