Vargha László et al. (szerk.): Beszámoló a Gyógyszeripari Kutató Intézet 10 éves működéséről 1950-1959 (Budapest, 1969)

Dr. Wix György: Mikrobiológiai eljárások a szteránvázas vegyületek szintézisében

вления. Стероидные соединения аллового ряда оказывают такое же действие, а соединения нормального ряда не обладают таким свойством. Переокисление подавляется также и эстроном.

Изучался также вопрос о том, нужна ли такому подавлению полная четырехкольцевая система. Было установлено, что она не нужна, и среди эффективных меньших молекул более подробно изучалось действие, бета-нафтола. Оказалось, что он непосредственно подавляет переокисляющую систему и с его помощью в разжиженных в 20—40 раз культурах образовавшийся уровень диендиона поддерживается в течение долгого времени. При наличии этого вещества, как только 75—80% прибавленного прогестерона или андростендиона превратилось в диендион, к культуре можно добавить дальнейшие количества субстрата. Практически, пятикратное прибавление оказалось наиболее подходящим; таким образом, в объеме 1 куб. м. удалось превратить 1 кг стероида в диендион, при приблизительно количественной продукции.

DR. GYÖRGY WIX

MICROBIOLOGICAL PROCEDURES IN THE SYNTHESIS

OF COMPOUNDS WITH STERANE SKELETON

History and significance of microbiological steroid transformations.

The microbiologist is faced with two kinds of problems, first, to search for strains capable of performing certain transformations, and second, to make a transforming organism applicable to industrial syntheses. This is a report of our work done in the field last mentioned.

We were concerned with mutation experiments on Aspergillus niger, Rhizopus nigricans and Cunninghamelia blakesleeana strains. For that purpose UV irradiation was employed, and the colonies which survived after a 99% degree of destruction, were assayed for their oxidizing capacity. Seemingly, the transfer of 11-a-oxy group to steroids mingles so intimately in vital functions that it is not to be abolished with XJV irradiation, whilst other types of oxydation can be made to cease more easily.

We succeeded in finding a fermentation method by which progesterone is converted to 11-a-oxyprogesterone with а 70 to 90% yield, and without steroid loss. Its essence consists in letting circulate an oxygen-saturated fermentation juice of some progesterone content, around the batch of the organism grown in form of pellets. From time to time, the liquid is let down to half or two-thirds and replaced with distilled water or fresh fermentation juice bearing steroid. Thus, progesterone is caused to attach to the colonies, and the resulting 11-a-oxyprogesterone is retained in the liquid. Since the latter is decanted at intervals, 6-/9-ll-a-dioxyprogesterone does not arise.

During microbiological preparation of Л-1,4-androstadiene-dione (“diene-dione”) this useful intermediate undergoes further oxidation. In connection with this process, we studied several compounds for their conversibility to diene-dione, for their mutual oxidability and overoxidation. Progesterone or d-4-androstendione, if given together with allo-pregnanedione, brings about a delay in diene-dione production, to let it later rise to higher a level which, besides, is not so far accessible to oxygenation (yielding Д-1- dehydro-testololactone) as it can be assumed from summing up the findings of the control flasks.

We designated this as ’’mixed substrate effect”, and were able to show it to be a peculiar case of non-competitive, irreversible inhibition. Only steroids of the alloseries were found to display that effect, those of the normal series were devoid of it.

Overoxidation is prevented by oestrone too. We tested, wdrether this inhibition wras due to the four ring system explicitly. This turned out to be incorrect, and of the minor but effective molecules /S-naphtol has aroused our main interest.

As proven by us, this molecule is a direct inhibitor to the overoxidation system and serviceable at a long-term maintenance of the diene-dione level existing in cultures diluted twenty- to forty-fold. In its presence, W'hen a 75—80% has already been converted from progesterone or androstendione to diene-dione, further substrate quantities can be added to the culture. In practice, a fivefold supply was found advantageous, and from each cubic metre of liquid 1 kg of diene-dione is gained at nearly quantitative conversion.

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