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On the relation between chemical structure and function in certain tumor promoters and antitumor agents

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Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques

Abstract

In recent months a great deal of interest has developed on the mechanism of action of tumor promoters and of certain antitumor drugs. In 1975, the hypothesis was published, based on stereochemical data [1], that the known (at that time) tumor promoters tetradecanoyl phorbol acetate (TPA) (and related active phorbol esters) and anthralin act via certain prostaglandin (PG) receptors as PG agonists. The prediction was further made that certain PGs themselves would be tumor promoters. This prediction has since been experimentally verified for PGE2 and PGFa [2]. We further hypothesized that certain antitumor compounds also acted via these specific PG receptors but as PG antagonists.

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Abbreviations

ala:

alanine

arg:

arginine

asp:

aspartate

CPK:

Corey-Pauling-Kaltun

cys:

cysteine

EGF:

epidermal growth factor

gln:

glutamine

glu:

glutamate

h-bond:

hydrogen bond

his:

histidine

ile:

isoleucine

leu:

leucine

lys:

lysine

lyso PE:

lysophosphatidylethanolamine

met:

methionine

N:

nitrogen

O:

oxygen

ODC:

ornithine decarboxylase

OH:

hydroxyl

PG:

prostaglandin

PG TP:

prostaglandin tumor-promoting

phe:

phenylalanine

pro:

proline

p/ser:

phosphoserine

TPA:

tetradecanoyl phorbol acetate

tyr:

tyrosine

val:

valine

A:

Arg

G:

glu

H:

his

I:

ile

(L):

left

P:

phosphate

PS:

phosphoser

π:

π-π interaction

(R):

right

RF:

receptor floor

PS/H:PS/I:I/H:

lipophilic interaction in lipophilic cleft between ile; β and methylenes of p/ser or his

Wavy line:

lipophilic interaction

→:

hydrogen bond, ionic bond, or ion-dipole interaction

—:

covalent bond (all epoxides shown in their broken state)

*:

site of interaction between members of a pair of interacting molecules Curved unbroken Une around an OH: a van der Waals’s/ion-dipole contact to phosphate

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Authors and Affiliations

  1. Department of Psychiatry and The Neuroscience Program, The University of Alabama in Birmingham, Birmingham, Ala., 35294, USA

    John R. Smythies M.D.F.R.C.P.

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  1. John R. Smythies M.D.F.R.C.P.
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  1. Basel, Switzerland

    Ernst Jucker

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Smythies, J.R. (1979). On the relation between chemical structure and function in certain tumor promoters and antitumor agents. In: Jucker, E. (eds) Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques. Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques, vol 23. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7105-1_4

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  • DOI: https://doi.org/10.1007/978-3-0348-7105-1_4

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-7107-5

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