| Mitomycin C (1), a representative example of a series of compounds termed the mitomycins, has found wide use in cancer chemotherapy. Extensive efforts to prepare new mitomycins with improved pharmacological properties led to the development of BMS-181174 (6) and KW-2149 (7). These compounds contain a disulfide aminoethylene unit and studies have indicated that their biological activities stem, in part, from the disulfide group. In this thesis, we incorporate this moiety within imino mitomycins (porfiromycins) and dimeric mitomycins.; Chapter II describes the synthesis and evaluation of the mitomycin imines, 7-N-(1′-amino-4′,5 ′-dithian-2′-yl)mitomycin C C(8) cyclized imine (56) and 7-N-(1′ -amino-4′,5′-dithian-2 ′-yl)porfiromycin C(8) cyclized imine (57). We synthesized 56 and 57 through 4,5-diamino-1,2-dithiane (62). We found that the rate of conversion of 57 to mitosene products was markedly enhanced upon Et3P addition and have attributed this to a phosphine-mediated disulfide cleavage process. This is the first example where a phosphine has been used to activate a mitomycin (porfiromycin). Addition of Et3P to DNA solutions containing 57 provided enhanced levels of DNA interstrand cross-links (ISC) compared with the reference compounds, porfiromycin (3) and 7-N -(1′-aminocyclohex-2′-yl)porfiromycin C(8) cyclized imine (59). This finding mirrored the rate studies. In the antiproliferative activity assay using the A549 cell line we learned that mitomycin imines 56, 57 and 59 displayed improved activities compared with 1 and 3, and only slightly lower activities than 7.; In Chapter III we report the synthesis and evaluation of mitomycins, 7-N,7′-N′-(1 ″,2″dithianyl-3″,6 ″-dimethylenyl)bismitomycin C (93) and 7-N7′-N′-(1 ″,2″-dithiocanyl-3″,8 ″-dimethylenyl)bismitomycin C (94), where two mitomycin units were tethered by a dithiane and dithiocane moiety, respectively. Synthesis of 93 and 94 proceeded through diamine meso-3,6-bis(aminomethyl)-1,2-dithiane (104) and 3,8-bis(aminomethyl)-1,2-dithiocane (125), respectively. We observed that Et3P dramatically enhanced the utilization of 93 and 94 but not the corresponding reference compounds, 7-N,7′- N′-(cyclohexanyl-trans-1 ″,4″-dimethylenyl)bismitomycin C ( 95) and 7-N7′-N ′-(2″,7″-dihydroxy-1 ″,8″-octanediyl)bismitomycin C ( 97). We further found that 93 and 94 provided higher levels of DNA ISC adducts than 95 and 97 upon addition of nucleophiles (Et3P, L-DTT). We have proposed that drug activation proceeds through a disulfide cleavage pathway. In the antiproliferative activity assay, 93 and 94 exhibited lower... |
