202
`
`Bréves communications ~ Kurze Mitteilungen
`
`Experientia XX/4
`
`absoluten Konfiguration von
`Ableitung der
`Alkaloiden der Aspidospermingruppe durch
`optischen Vergleich mit Alkaloiden der
`Strychningruppe
`
`In einer kiirzlich veréffentlichten Mitteilung! wurde
`durch chemische Korrelation mit den in ihrer absoluten
`Konfiguration bekannten stark linksdrehenden Alkaloi-
`den 19, 20-Dihydroakuammicin (I) und Tubifolin (II) ge-
`zeigt, dass den stark rechtsdrehenden Basen Tubotaiwin
`(= 19, 20-Dihydrocondylocarpin)
`(III) und Condyfolin
`(IV) die nachstehende absolute Konfiguration zukommt.
`
`Strukturell und damit in ihrem molekularen Bau sehr
`nahe verwandt mit Tubifolin und Condyfolin sind das
`stark rechts- bzw.
`linksdrehende (+)* und (—)%-1,2-
`Dehydroaspidospermidin (V)4.
`(~—)-V zeigt
`eine
`ahnliche Molekularrotation wie
`Tubifolin und der (bisher in der Natur noch nicht ange-
`troffene) Antipode von Condyfolin. Diese drei Stoffe be-
`sitzen dasselbe chromophore Zentrum. Wodieses Zentrum
`auch immerist, es lassen sich daran réumliche Oktanden
`anlegen, die in allen drei Verbindungen die gleichen zum
`Zentrum ndchstgelegenen Substituenten in den gleichen
`Oktanden enthalten. Dem (—)-1, 2-Dehydroaspidospermi-
`din lasst sich daher die absolute Konfiguration V (dem
`rechtsdrehenden die spiegelbildliche) zuschreiben.
`Die Bildung von (+)-Quebrachamin® aus (—)-V zeigt,
`dass dem ersteren die absolute Stereochemie VI zukommt.
`(—)-Aspidospermin besitzt am C-5 die gleiche absolute
`Konfiguration wie (~—)-Quebrachamin®, so dass ihm die
`absolute Kenfiguration VII zugeschrieben werden kann.
`(—)-Vincadifformin® ([M]p =—1821°) geht durch De-
`carbomethoxylierung in (—}-V iiber und besitzt daher die
`absolute Konfiguration VIII®.
`Zur Zeit wird versucht, durch RD-Messungen unter
`Heranziehung weiterer Relais-Substanzen den vorge-
`schlagenen
`konfigurativen Zusammenhang
`zwischen
`Strychnin- und Aspidosperminalkaloiden zu erharten’.
`
`Summary, The absolute configuration of certain alka-
`loids of the Aspidospermin group is suggested.
`
`D. ScHUMANN,
`B. W. Bycrort und H. Scumip
`
`Organish-Chemisches Institut der Universitdt, Ziivich
`(Schweiz), 27. Dezember 1963.
`
`1 DP. Scaumann und H. Scumip, Helv. chim, Acta 46, 1996 (1968).
`2G. F. Smrra und M. A. Wautp, J. chem, Soc. 1963, 4002. Das (+)-
`1,2-Dehydroaspidospermidin zeigt (ooleOR = ++ 243°,
`3M. Prat, J. LE Men, M.-M. Janot, J. M. Witson, H. Bupzixre-
`wicz, L. J. Duruam, Y. NAxacawa und C, Djerassi, Tetrahe-
`dron Letters No. 7, 271 {1962}. (—)-1,2-Dehydroaspidospermidin
`zeigt [a]sOH — — 225°,
`4 Fir die relative, der stabilsten Anordnung entsprechende Kon-
`figuration dieses Alkaloids existieren gute Argumente: ®, sowie G.
`Stork und J. E. Dotrini, J. Amer. chem. Soc. 85, 2872 (1963)
`(Fussnote 9).
`IX, Bremann und G. SpireE.iter, J. Amer, chem. Soc, 84, 4578
`(1962).
`® Die franzésischen und amerikanischen Autoren haben auf Grund
`von NMR-Argumentenfiir das Alkaloid das gespannte System mit
`cis-Stellung des H-Atoms am C-13 und der Athylenbriicke am
`C-12 vorgeschlagen, was die Molekiilgestalt gegeniiber einer
`trans-Anordnung deutlich verandert; vgl. hierzu®,
`7 Dem Schweizerischen Nationalfonds danken wir fiir Unterstiit-
`zung.
`
`5
`
` 1
`
`LN
`LH
`
`re
`COOCH,
`Tubotaiwin (IIT)
`(MIGHC» + 1936°
`
`COOCH,
`19, 20-Dihydroakuammicin (I)
`[MIGHsOH _ aogs°
`
`
`
`Tubifolin (11); (MIEH#08 — gay°,
`in CHCl, — 911°, in Essigester — 962°
`
`Condyfolin (IV)
`}
`rmyEssigester +. 927°
`
`
`
`(— )-I, 2-Dehydroaspidosper-
`midin (V): [MJGeH#OH _ gaye
`
`{+)-Quebrachamin (VI)
`
`
`
`Hd A
`
`4
`
`(—)-Aspidospermin (VI1)
`
`xa
`
`cock,
`
`(— )-Vincadifformin (VIIT}
`cmype4s0H _ igaie
`
`5-Azacytidine, a New, Highly Effective
`Cancerostatic
`
`In the course of studies on the azapyrimidines as poten-
`tial inhibitors of nucleic acid biosynthesis, a method for
`the synthesis of nucleosides derived from 5-azacytosine
`has recently been developed in the laboratories}.
`Biological testing of these compoundshas revealed that
`the cytidine analogue, 5-azacytidine (5-AzCR, m.p. 230°),
`has significant antimetabolic and cancerostatic effects.
`
`‘The substance, in very small concentrations, inhibits the
`growth of some bacteria. Thus the growthof E. colt Bina
`synthetic medium is inhibited to the extent of 50% at
`concentrations of 0.25 wg 5-AzCR perml, in strong contrast
`to a weak bacteriostatic effect (50% growth inhibition at
`520 ug per ml) shown by the 6-azacytidine which also
`
`1 F, Sorm and A, Pisxata, Coll, Czech. chem. Commun., in press. -
`Czechoslovak patent application No. PV 5916-63 and PV 7093-63.
`
`CELGENE 2116
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`iS. IV. 1964
`
`Brevi comunicazioni — Brief Reports
`
`203
`
`Table I. Effect of 5-azacytidine on lymphoid lenkaemia in AK inbred
`tice
`
`
`Table II. Effect of various cancerostatic substances on lymphoid
`leukaemia in AK inbred mice
`
`
`Doseof 5-azacytidine
`No.of leukaemic deaths
`% 20-day
`and no, of doses i.p.
`after 20 days
`survivors
`
`
`Dose and no. of
`% response®
`Substancetested
`dosesi.p.
`
`
`100 mg/kg 1
`
`10 mg/kg 5 x,
`alternate day schedule
`
`14/8
`
`o/s
`
`75»
`
`100
`
`87.5
`15/8
`5 mg/kg 7 x, daily
`
`
`4-Amino-pteroyl-
`glutamic acid
`
`5-Bis-(2-chloroethyl)-
`aminomethyluracil
`6-Azauridine
`
`0.250 mg/kg 4 x,
`alternate day schedule
`
`0.250 mg/kg 9 x,
`daily
`500 mg/kg 6 x,
`daily
`
`30.5
`
`16
`
`836.6
`
`il
`10 mg/kg 7 x,
`6-Mercaptopurine
`
`daily
`riboside
`Eight control mice died after 6.6-- 0.5 days of leukaemia. Therapy
`repENRt
`initiated always 24 h after inoculation of leukaemic cells (107). —
`“18th day after inoculation. » 1 mouse died on the tenth day of
`intestinal haemorrhage, lymphoid hypoplasia and bone-marrow de-
`pression without macroscopical or cytological signs of leukaernia.
`
`® Response is given in % increase in survival time. Therapyinitiated
`always 24 h after inoculation of leukaemic cells (10*).
`
`possesses cancerostatic activity. Another cancerostatic of
`the same type, 6-azauridine, inhibits the growthof E. coli
`B by 50% at 1300 ug per ml. The inhibitory effects of
`5-AzCRon E.coli can be reversed by uracil, uridine and
`cytidine; this clearly indicates that 5-AzCR is interfering
`with the biosynthesis of the pyrimidine components of
`the nucleic acids or with their incorporation into bio-
`polymers.
`5-AzCR is somewhat toxic to mammals. In mice of in-
`bred strain AK, the acute toxicity (LD,,) is about 150
`mg/kg. Depression of the bone marrow and the hypo-
`plastic involution of the lymphatic system are the main
`toxic manifestations.
`In agreement with these effects, the new antimetabolite
`is a potent inhibitor of the lymphoid leukaemia of the in-
`Institute of Organic Chemistry and Biochemistry,
`bred AK mice (Table I). It is remarkable that even a single
`Czechoslovak Academy of Science, Prague (Czechoslovakia),
`dose (100 mg/kg), though provoking some toxic effects,
`January 3, 1964.
`increases the survival time very considerably. The leu-
`
`
`kaemia of AK mice is relatively resistant to chemo-
`therapy, especially as compared with lymphoid leukaemia
`L1210. For comparison, the effects of various well-known
`cancerostatic agents on AK leukaemia, as determined in
`our laboratory, are listed in Table IT.
`An extensive investigation of the new cancerostatic
`substance, including clinical trials, is under way.
`
`Zusammenfassung. Die hohe bakteriostatische und can-
`cerostatische Wirkung eines neuen Antimetaboliten, 5-
`Azacytidin, wird beschrieben.
`
`F. Sor, A. PisKata,
`A, CrmAx, and J. VESELY
`
`Reaction of Gold with Collagen in vivo
`
`Gold in the form of thio-complexes is successfully used
`in the treatment of rheumatoid arthritis, one of the so-
`called collagen diseases. Although this method of treat-
`ment is comparatively old, the mode of action of gold
`complexes has not been definitely elucidated. As it can be
`assumed that reaction of gold compounds with collagen
`is similar to that of other heavy metals, we have tried to
`prove experimentally the binding of gold into the collagen
`structure.
`For this purpose collagen fibres from tail tendon of rats
`(RTT) of Wistar strain (Rattus norvegicus var. alba),
`treated with gold sodium thiosulfate (‘Sanocrysin’ —
`Dansk Chemoterapeutisk Selskab, Denmark), 2 mg/100 g
`of body weight per week, were subjected to electron
`microscope observations and to measurements of tem-
`perature of shrinkage!, swelling*, and contraction-relaxa-
`tion?.
`We have found that, in the electromicrograph of RTT
`collagen from a rat treated for 18 weeks with Sanocrysin,
`three dark bands can be detected, two of them appearing
`
`comparatively dark. These two bands, 60 and 100 A units
`wide, are 60 A units apart, The third band in the middle
`of the light band is 30 A units wide (Figure 1). As far as
`we are informed from the literature, this is the first case
`of electron microscope demonstration of the binding of
`gold with collagen under conditions in vive.
`Other methods used in our experiments were to prove
`the binding of gold with collagen in the earlier stages of
`the treatment. With the use of all methods mentioned
`above, distinct changes in the measured quantities were
`observed even after first injections of gold (Figures 2-4).
`From the results obtained, it can be assumed that inter-
`action of collagen with gold is principally similar to
`
`1G. C. Nutting and R. Borasxy, J .Amer. Leather chem. Assoc.
`48, 96 (1948),
`% J. Poucuiy and I. Vavrucn, Physical Chemistry of Colloid Sys-
`tems (SNTL, Prague 1960, in Czech.),
`8 Z. Devi and J. Rosmus, Report at the I. Conference on Collagen
`Proteins (Velke Karlovice, September 1963).
`
`