Synthesis and biological activities of new 2-imidazoline derivatives

Podium Presentations-Medicinal

Chemistry

S83

I Eur. J. Pharm. Sci. 4 Suppl. (1996) S83-S84

clonidine

The well known drugs such "

ox

nr~~~~ldiru

that

structure have bean d-trated to act aa a,[email protected], recently centrally nadiatad anti-rtenaiva sc~lon of theas compuda ia belived to be mediated by is difficult to dirrociate I, imidaaolina rrcaprorr. It

have

Recently, we reported our studies with compounds,containing aMwncene OTacridine covalently linked, at position-Q,through an amide bond to spermine affording conjugateswith biinctional modes of DNA binding (Adlam et al. 1994; Rodger et al. 1994; Carrington et al. 1996). These compoundswere cytotoxicagainst 616 murine melanoma cells. We now report novel acridine conjugates which were synthesised by N-alkylation at position-9 by spermine or by spermine linked to one or two molecules of 5-aminovaleric acid. These 5aminovaleric acid units were incorporatedin the conjugates in order to introduce a region offlexibilitybetween the acridine and the spermine, allowing the two binding regions to optimise their interactions. In order to minimize side reactions, spermine was protected on three amine groups with benzykntycarbonylgroups (Canington et al. 1996) leaving one free terminal amine. Spermine acylations were carried out uiing DCC as the coupling (dehydrating)reagent and HOBt (cat.). N-Alkylations onto acridine were achieved by the displacement of phenoxide from Sphenoxyacridine in molten phenol (16 h). The polyamine conjugate was finally deprotected by hydrogenolysis. These synthetic 9-aminoacridine conjugateswere assayed on B16 murina melanoma cells in the tetrazolium microtitreplate (MIT) assay as described by Mosmann (1963). The spennin&-acridine conjugate showed an EC50 of 2.3xltVM, an order of magnitude better than any of our amide conju9etes previouslyreported (Carrirgton et al. 1996). The conjugate with one spacer had a similar EC50 of 3.2~10% The Mmpound with two spacers had an EC50 of 5.6x10-%4, showing it to have significantlyless activity than either of the other two conjugates.

imidaaolti

an

receptors

iinidaaolina molecular

level

from

Uaucturo

imidarolina

a,-adrenoraceptorr

axbibit

the availability

Therefore. vith

they

am

an0

Of

dagrer

the

at

rimilarity.

Of ns* MmlypertrMiw agentn rtimulaea further reaauch rubtile ?? trucWre of theaa two rbould

towarda elucidating tha receptor clurea. In Chia cawnication tha aynthoaia, crystal and molecular structure 01 veil M biological activkirr of the itidaroline derivativea

?,

3 and 4 will

be diawred

in

detail.

Adlam, G. et al. (1994) Bioorg. Med. Chem. Lett. 4: 24352440 Carrington, S. et al. (1996) Pharm. Sci. 2: 25-27 Mosmann, T. (1963) J. Immunol.Methods 65: 55-63 Rodger, A et al. (1994) Biopolymers34: 1563-l 594

Bolaamphiphilic lipids are the constituents of the membranes of archaebacteria which have surprisingly stable membranes. In continuation of our previous works on the synthesis and biophysical/biochcmical studies of glycolipids [ 1,2]. we are interested to use bipolar glycolipid systems with two sugar moieties at both the ends of a long hydrophobic chain with or without ethoxy unit as spacers. The required starting material a, o-dials 2 are prepared tbrougb the condensation of the corresponding lower homologues in four steps. Monoetberification with tetra- or penmethylene glycol can be achieved starting from a,o-dibromides, obtained by bromination of the corresponding a. odials. .sup HO(CH2)xOH

-

Heam”

HO(CH2)nON -

HO(CH&,$JH

2

Br(CH,),,Br %W”p,O!&

HO(CH&w’JH

HO(CH2CH20),,,/

W2h

pA,

n =

19

where

Se,,

oxygen

is

IIT_ 2)“MW

f!-Gly-O(CH2CH2O~m/(cH2)n

WB4101

1 ..0. m-l2.X m-4c.I. ..llrr,l

oxygen

difference

of energy and

to

the

on

ring

a derivative,

1Ai?,,,,,,

13 9

= 0838

1

s = 0439

F = 416

superdelocalisability

on

the

side-chain,

is

the

carbon

of the highest

atom attached

and Dw

2,

Sn,

benzodioxan nucleophilic

1AEHOMO 1 is the

occupied

of

between betweenthe chain

molecular

is the distance

10 the methoxy-substituted

modulus

orbital

ring and the farthest non-

atom para to that oxygen

equation

indicates

0 018 SnU-

Q2

electrophilic

adjacent

superdelocalisability

hydrogen

= 0 274 SQ,-

r-’ = 0 922

BGly-O(CH2CH20),,,\

A.lbgd.KAu~uabF. Wilhdm.S.KaIaaajamdP.Nuhn.Archiv Phamz. 326(1993)&(8. P. Nuhn.T. PM. 0. Bedas. F. Wilhelm S.K.Chsaaja.ibid,327. (1994) 429. S.K:Chu~. F. Wilhelm. P. Nuhh Eur. 1. Ph Sci. 2 (L994) 95. F. Wilhelm. S.K.Chatterjee.B. Ratmy, P. Nuhn. R. Bmske and I. Or&vein, Licbip Am.. (19%) 1673

We

H3CYo have carried out a quantitative structure-activiry relationship (QSAR) study of 19 derivatives, with the aims of improving potency and elucidating the drug-receptor interaction The best correlation obtained was’

The I. 2. 3. 4.

structureshownbelow.

has the

HWCHzCHzO),\

As was done in our previous works 13.41 the reaction of pentaacetyl monosaccharide (GlycAc,; glyc- = Glc, Man. Gal) 1 with a.o-dials 2 in presence of triflale and molsieves lead to stereospecific j%aoomer 3 (trclnsglycosidation) in good yields.

ClycAcS + 2 v

wB4101 is a potent al-blockerwhich

the

adrenoceptor

permits key

the prediction

interaction

points

of compounds of

the

of high potency,

compounds

with

the

and a,

’