The Mitomycins and Porfiromycins

J. WILLIAM LOWN and GORDON L. WEIR. Can. J. Chern. 56, 249 (1978). The base-catalyzed methanolyses of 1-methylgramine methiodide 2, I-niethylisogramine lnethiodide 3, and 1-methylindol-2-ylmethyl N-fert-butylcarbamate 4 were studied in the temperature range 50-90°C in order to gain information about the relative reactivity of 2-and 3-indolylcarbinyl systems, analogous to the proposed reactive sites of the mitosane antitumor antibiotics when enzymatically reduced. The leaving groups were also analogous to those found in the mitosanes. The methanolysis of 2 proceeds with strict first-order kinetics in accord with indole nitrogen lone pair assistance of the displacement. The comparable reactions of 3 and 4 proceed with second-order kinetics in accord with a direct Ss2 process and the carbamate moiety is the better leaving group by a factor of 10. Gramine methiodide 5 undergoes a very + rapid elimination of the elements of (CH3),NH I-followed by addition of a nucleophile such as methanol at a rate which is too rapid to follow kinetically even at -78'C. In accord with the model for the mode of action of the mitosanes, 2.2 m M 5 alkylates and cross-links DNA to the extent of 71% at p H 7 and 37°C. The extent of cross-linking is proportional to the (G + C) content of DNA's as was found for the niitosanes and occurs at a position other than N-7 on guanine. The results suggest that in the reaction of the mitosane antibiotics with DNA the inherent greater reactivity of the 10-carbamate moiety towards nucleophilic displacement is more than offset by the rate enhancement of the 1 position due to relief of aziridine ring strain. Chem. 56, 249 (1978). On a ttudie la mCthanolyse, catalyske par les bases, de I'iodomethylate de nitithyl-1 grarnine (2), de I'iodomethylate de methyl-1 isogramine (3) et du N-trrf-butylcarbamate de methyl-l indolylmethyle-2 (4) a des temperatures allant de 50-90°C; on a realis6 ces etudes afin d'obtenir des inforniations concernant les rCactivitCs relatives des systenies indolylcarbinyles-2 et -3 qui, lorsqu'ils sont reduits d'une f a~o n enzymatique, sont des sites riactifs proposes pour les antibiotiques antitumoraux mitosanes. Les nucleofi~ges sont aussi analogues a ceux trouves dans les mitosanes. La rnethanolyse de 2 se produit d'apres line cinetique de preniier ordre strict tel que prevu si I'on fait I'hypothese que la paire d'ilectrons libres de I'azote de I'indole fournit ulie aide lors du deplacement. Les reactions cornparables de 3 et 4 se prod~lisent suivant des cinetiques du deuxieme ordre tel que I'on peut le supposer pour une reaction SN2; par opposition au groupe iodomethylate le groupe carbamate est un meilleur ~iuclCofiige par un + facteur de 10. L'iodomCthylate de gramine 5 subit une elirninatio~i tres rapide de (CH3),NH 1-qui est suivie par une addition de nuclCophiles, comlne le methanol, a une vitesse qui est trop rapide pour &tre mesurke mCme a -78°C. Tel qu'on peut le supposer en se basant sur le niodele pour le mode d'action des mitosanes, le compose 5, a des concentrations d...

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Studies related to antitumor antibiotics. Part XIII. Reactivity of 2- and 3-indolylcarbinyl compounds as models for mitosane action

Lown¹,

Weir²

1978

“…The reduced form of the aziridinomitosene (4) is then considered "activated", i.e., capable of rapid bifunctional alkylation and hence covalent cross linking of DNA (2). A possible clue to the origin of the 9a moiety and the biosynthetic formation of rings B and C in the mitosanes is provided by the pyrrolizidine alkaloids which they resemble in structure and function (Scheme 2) (2, 8-10).…”

Section: Citrullinementioning

confidence: 99%

Studies Related to Antitumor Antibiotics. Part III. Syntheses of 1,2,3,4,5,6-Hexahydro-2,3-benzazocin-5-ones as Possible Intermediates in the Biosynthesis of Mitomycins

Lown¹,

Itoh²

1975

J. WILLIAM LOWN and TSUNEO ITOH. Can. J. Chern. 53,960(1975). The synthesis of 8-rnethoxy-9-rnethyl-N-p-toluenesulfonyl-l,2,3,4,5,6-hexahydro-2,3-benzazocin-5-one (23) and its conversion via transannular interaction to the 2,3-dihydro-1H-pyrrolo-[1,2-alindole ABC parent ring system of the antitumor antibiotic rnitornycin C is described. The possible implication of this result in the biosynthesis of the rnitosanes and the connection with the structurally and pharmacologically related pyrrolizidine alkaloids is discussed. Chern. 53,960 (1975). On dicrit la synthese de la rnkthoxy-8 rnithyl-9 N-p-toluenesulfonylhexahydro-1,2,3,4,5,6 benzazocin-2,3 one-5 (23) et sa conversion, par l'intermidiaire d'une interaction transannulaire, en dihydro-2,3 IH-pyrrolo[l,2-alindole qui cornporte le systerne cyclique A B C du cornposi antitumoral et antibiotique rnitornycin C. On discute de I'irnplication possible de ces risultats dans la biosynthese des rnitosanes et la relation avec les alkaloides pyrrolizidine qui leur sont relies tant au point de vue de la structure que de la pharmacologie.[Traduit par le journal]

“…856 (1973) The Mitosane class of potent antitumor anti-synthesized and the mode of action is not fully biotics 1 isolated in 1956 (1) from Strepionlyces understood, preventing rational structural modicaespitos is in clinical use in Japan in the control fication to enhance antitumor properties (3,4). of tumors (2).…”

mentioning

confidence: 99%

Studies Relating to Aziridine Antitumor Antibiotics. Part I. Asymmetric Syntheses. Part II. Chiral Aziridines and their Conversion to α-Aminoacids

Lown¹,

Itoh²,

Ono³

1973

Separable diastereomeric cis-1-menthyl 2-phenyl-3-aziridinecarboxylates (4 and 5) were prepared by the Gabriel reaction. N-Acylation with p-nitrobenzoyl chloride or p-anisoyl chloride of 4 and 5 gives 7 and 8, and 23 and 24, respectively. Sodium iodide-catalyzed rearrangement of the N-acylated aziridines is rcgiospecific with exclusive attack at C-2 and from 8 is obtained the chiral 2-oxazolines cis-9 and trans-10 in a ratio of 30:70 together with the unsaturated amide 11. The structure of the latter was proven by independent synthesis. The intermediate I-menthyl N-p-nitrobenzoyl-3-iodophenyl-alaninate (18) was isolated at lower temperatures and shown to form the equilibrium mixture of 9 and 10 with triethylamine owing to partial racemization by a Finkelstein identity reaction. Use of an N-p-anisoyl substituent in the aziridine improves the yield of chiral 2-oxazolines by preventing the formation of 11, and allows the separation of pure cis-and trans-oxazolines for characterization. The aziridines bearing N-p-anisoyl substituents display a greater sensitivity to attack by weaker nucleophiles than thep-N-nitrobenzoyl analogs.Acid hydrolysis of 9 and 10 gives D-allo-a-phenylserine in an optical yield of about 17% from which 5 and 8 are tentatively assigned the 2R,3R configuration. Similar acid hydrolysis of the 2-p-anisyl-2-oxazoline (266) allowed the isolation of the interrnediatc I-menthyl 0-anisoyl-allo-p-phenylserinate (30a), hydrolysis of which gave D-allo-p-phenylserine in about 18% optical yield. The isolation of alloa-phenylserine only from cis-and trans-2-oxazolines is attributed to acid-catalyzed inversion at the benzylic center to the conformationally more stable allo form.