Gh. Hakimelahi et al., Design and synthesis of a cephalosporin-retinoic acid prodrug activated bya monoclonal antibody-beta-lactamase conjugate, BIO MED CH, 9(8), 2001, pp. 2139-2147
Two novel series of all-trans-beta -retinoic acid derivatives were synthesi
zed and found to possess anticancer activity. The first series, cephalospor
in 3 ' -retinoic esters 6 and 7 were, respectively, obtained by the condens
ation of all-trans-beta -retinoic acid (2) with cephalosporins 4 and 5. The
second series, 7-(retinamido)cephalosporins 11 and 12, were synthesized, r
espectively, by the condensation of 2 with cephalosporins 9 and 10. These f
our heretofore undescribed compounds 6, 7, 11, and 12 showed inhibitory act
ivity against murine leukemias (L1210 and P388), sarcoma 180, breast carcin
oma (MCF7), and human T-lymphocytes (Molt4/C8 and CEM/0). They also inhibit
ed squamous metaplasia and keratinization in tracheal or.-an cultures deriv
ed from vitamin-A-deficient hamsters. Moreover, cephalosporin 3 ' -retinoic
ester 7 exhibited enhanced activity against keratinization with ED50 = 3.9
1 x 10(-11) M in the presence of a beta -lactamase from Staphylococcus aure
us 95. A tumor targeting fusion protein (dsFv3-beta -lactamase) was also us
ed in conjunction with cephem-based retinoid 7 and the potency of 7 toward
L1210, P388, and MCF7 was found to approach that of the free retinoic acid
(2). In the presence of dsFv3-beta -lactamase, tumor cells were found to be
much more susceptible to retinoid 7 than normal human embryonic lung cells
. These notions provide a new approach to the use of beta -retinoic acid fo
r antitumor therapy. (C) 2001 Elsevier Science Ltd. All rights reserved.