Serine Derivative with Antitumor Activity

Levi, Irving; Blondal, Harold; Lozinski, Ezra

doi:10.1126/science.131.3401.666

Cited by 18 publications

(5 citation statements)

References 2 publications

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“…N-dichloroacetyl DL serine, reported by Levi et al (1960) to cause regression of sarcoma 37 in mice, had no effects, either cytological or developmental, at any of the concentrations tested (1-0.005 mg./ml. ), except that there were some ciliary defects in a few of the experimental larvae observed the day following treatment.…”

Section: Treatment Of Chaetopterus Eggs With Niitmnycin C N-dichloroa...mentioning

confidence: 83%

The Cytological Effects of Podophyllin and Podophyllotoxin on the Fertilized Eggs of Chaetopterus

Henley

Costello

1965

The Biological Bulletin

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Section: Treatment Of Chaetopterus Eggs With Niitmnycin C N-dichloroa...mentioning

confidence: 83%

The Cytological Effects of Podophyllin and Podophyllotoxin on the Fertilized Eggs of Chaetopterus

Henley

Costello

1965

The Biological Bulletin

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“…This substance did not show antibacterial activity. Other workers subsequently also synthesized the compound and found it to possess appreciable antitumor activity in mice (LEVI et al, 1960).…”

Section: Structure-activity Relationshipsmentioning

confidence: 98%

Antibiotics

1967

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AII rights, especially that of tnmslation into foreign languages, reserved. It is also forbidden to reproduce this book, either whole DedicationFor most areas of scientific pursuit, there is usually that rare investigator who has the imagination to conceive ideas, who has faith in his visions, and who has the ability to critically test his concepts in the laboratory. Almost invariably, this scientist also inspires younger men to enthusiastically enter into his research program. To him should go the accolades and the recognitions of the esteem in which he is held. As only a small part of this esteem, we wish to dedicate these books to Professor SELMAN A. W AKSMAN in appreciation of his leadership and contributions in all facets of antibiotic research. PrefaceThe idea for publishing these books on the mechanism of action and on the biosynthesis of antibiotics was born of frustration in our attempts to keep abreast of the literature. Gone were the years when we were able to keep a bibliography on antibiotics and feel confident that we could find everything that was being published on this subject. These fields of investigation were moving forward so rapidly and were encompassing so wide a range of specialized areas in microbiology and chemistry that it was almost impossible to keep abreast of developments. In our naivete and enthusiasm, however, we were unaware that we were toying with an idea that might enmesh us, that we were creating an entity with a life of its own, that we were letting loose a Golom who instead of being our servant would be our master.That we set up ideals for these books is obvious; they would be current guides to developments and information in the areas of mechanism of action and biosynthesis of antibiotics. For almost every subject, we wished to enlist the aid of an investigator who himself had played a part in determining the nature of the phenomena that were being discussed. One concept for the books was that they include only antibiotics for which a definitive, well-documented mechanism of action or biosynthetic pathway was known. Yet, such an approach would not entirely serve the purpose we projected, for it would not encompass all of the information available in these fields of antibiotic investigations and blind searches for the original literature would still have to be made. We therefore chose to include any and all antibiotics about which some pertinent information had been published. It was obvious even at the start that such a compilation, integration, and analysis of information could never be complete unless scientific investigations ceased at the moment the last manuscript was submitted-an end that was neither desirable nor possible. An addendum was therefore included at the end of the volume and left open for the addition of new information until the last pages of the regular articles had been printed.The original concept has also been further expanded as the authors of several papers found it advisable to elaborate on their subject. Some of the articles included discussions...

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“…The coinpo~~ncl is non-toxic to mice in doses LIP to 4 grams per liilo of bocly weight. A preliininary report of these results has been published (37).…”

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confidence: 96%

N-Dichloroacetyl Derivatives of Serine and Threonine and of Their Esters and Sodium Salts

Levi¹,

Koller²,

Laflamme³

et al. 1960

Can. J. Chem.

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The N-ciichloroacctyl derivatives of DL-serine and DL-threonine were prepared by the Schotten-Baumann reaction from the amino acids and dichloroacetyl chloride. Negative ninhydrin tests coupled with elementary analyses indicated that only the amino group was acylated. The ester derivatives of these con~pounds were prepared either by esterilication of the N-dichloroacetyl-DL-amino acid with diazomethane or by the reaction of the amino acid ester with dichloroacetyl chloride in the presence of triethylan~ine. The sodium salts and the esters \\-ere tested for antitumor activity against sarcoma 37 ill 11lice and \lrallrer carclnonla 256 in rats. In both cases regression of the tumors was obtained.The original studies of Cornman (1) and of Stoclc, Sugiura, and Rhoacls (2) clemonstratecl that certain antibiotics obtainecl from the culture filtrates of bacteria and molds inhibited the growth of transplanted tumors in animals. NIany other worlcers have since reported on the antitumor activity of a variety of antibiotic substances (:3-16). Two of these antibiotics, azasel-ine (0-diazoacetyl-L-serine) (15) and DON (6-diazo-5-0x0-Lnorleucine) ( l 6 ) , \vl~ich were isolated from the culture filtrates of two species of Stueptomyces, and which retarded the growth of sarcoma 180 in the mouse, are diazo a~lliilo acids. This is ilote\vorthy because a search for amino acid derivatives which might serve as a~ltago~lists in the ~lletabolis~n of tumor cells, first suggested b~. Greenberg a11d Schulman (1.7), has bee11 going on for many years.I11 view of the above, it was reasoned that if sollle of the common amino acids were modified to cor~tain an essential portion of a natural antibiotic, antimetabolites useful for cancer chemotheraphy might result. Since it is generally believed that chloramphenicol is a specific inhibitor ol protein synthesis (18), and since the N-dichloroacetyl group is esse~~tial for its maxiinurn antibiotic activity (I 9), it seemed logical to modify the structure of amino acids with the N-dich1oroacet)-l radical in an attempt to achieve this aim.A number of N-dichloroacetyl amino acids were therefore prepared and investigated for their pharmacological activities particularly with respect to their antitumor ancl ailtibiotic effects. In this paper only sel-ine and its homologue, threonine, are considered because there is a close structural relationship between their 3-dichloroacetyl derivatives (In and IIa respectively) and cl~loramphenicol (I1 I ) , ancl also because of the unique biological position seriile occupies in the metabolism of normal cells (20)(21)(22)(23)(24)(25)(26)(27)

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Serine Derivative with Antitumor Activity

Cited by 18 publications

References 2 publications

The Cytological Effects of Podophyllin and Podophyllotoxin on the Fertilized Eggs of Chaetopterus

The Cytological Effects of Podophyllin and Podophyllotoxin on the Fertilized Eggs of Chaetopterus

Antibiotics

N-Dichloroacetyl Derivatives of Serine and Threonine and of Their Esters and Sodium Salts

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