Synthetic procedures have been developed which lead to the 2-aza congeners 3 and several related N-oxides 4. The analogues 3 exhibited a wide range of in vitro cytotoxicity against L1210 leukemia, the human colon adenocarcinoma cell line LoVo, and the doxorubicin resistant LoVo/DX cell line. Selected analogues of 3 showed significant P388 antileukemic activity in mice with 3c exhibiting high activity. This activity was also retained in the related N-oxide 4a. These heterocyclic bioisosteric models are representative of the first anthracene-9,10-diones which display antileukemic activity comparable to mitoxantrone.
Cocaine is one of the most widely abused psychostimulants, causing major medical and socioeconomic problems (1). Currently, there is no effective treatment against cocaine addiction available; therefore, clarifying the molecular mechanisms underlying the psychostimulatory effects and addictive properties of cocaine should prove critical for potential development of future therapeutic strategies. Cocaine and related drugs act by inhibiting clearance of released monoamine neurotransmitters from the synaptic cleft (2-4). This clearance of monoamines occurs via three distinct but highly homologous monoamine transporters, the serotonin transporter (SERT), 1 the dopamine transporter (DAT), and the norepinephrine transporter (NET) (2-4). Cocaine binds with high affinity to all three transporters and is generally believed to act as a competitive blocker of substrate translocation (4, 5). Several studies have provided evidence that inhibition of the DAT is the predominant mechanism behind the stimulatory effects and addictive properties of cocaine (6 -8). However, this hypothesis has been challenged by recent studies on mice in which the DAT gene has been deleted (1). Despite the absence of the DAT gene, it was surprisingly observed that these mice self-administered cocaine, indicating a possible important role of also the SERT and NET (9, 10).The SERT belongs together with DAT and NET to a family of Na ϩ /Cl Ϫ -dependent solute carriers that are characterized functionally by their dependence on the presence of Na ϩ and Cl Ϫ in the extracellular fluid (3, 11). All Na ϩ /Cl Ϫ -dependent carriers are believed to share a common topology characterized by the presence of 12 transmembrane segments connected by alternating extracellular and intracellular loops with an intracellular location of the N and C terminus (3, 4, 11). Despite intense efforts, including many mutagenesis studies (12-18) and studies using photoaffinity labeling (19), surprisingly little is known about the binding site for cocaine-like substances in the monoamine transporters. Although cysteine-scanning mutagenesis of transmembrane segment 3 in the SERT has suggested that two residues in the middle of the transmembrane segment could be in close proximity to the cocaine binding site (20), no direct contact sites have been established between cocaine and specific transporter residues.
Naturally occurring quinones which structurally consist of an anthracene-9,10-dione chromophore are important antitumor agents. The anthracycline antibiotics, in particular, doxorubicin, are major chemothera
peutic agents. The pluramycins and the ene-diynes antibiotics also show pro i mise as antitumor drugs. The synthetic anthracene-9,10-diones such as mitoxantrone are potent antitumor agents. Analogues related to mitoxantrone have been synthesized and biologically evaluated. Aza and diaza bioisosteres related to the anthracene-9,10-diones have
been prepared and evaluated and several of these chemotypes show promise for development as anticancer agents. This review will discuss the discovery of cytotoxic anthracene-9,10-diones and the synthesis and antitumor properties of the related aza and diaza bioisosteres.
The synthesis of 6,9‐difluoro substituted benzo[g]quinoxaline‐5,10‐diones (3A), benzo[g]quinazoline‐5,10‐diones (3B) and benzo[g]phthalazine‐5,10‐diones (3C) have been accomplished. Treatment of 3A, 3B or 3C with diamines or N‐(t‐butoxycarbonyl)ethylenediamine led to the corresponding 6,9‐bis[(aminoalkyl)amino]‐substituted analogues related to 2A, 2B and 2C, respectively. The mono‐substituted derivatives 4h and 4i could be isolated from displacements commencing from 3A. A competitive ring‐opening of the pyrimidine ring of 2C occurred during the reaction with N,N‐dimethylethylenediamine. Removal of the BOC‐protecting group from 2Ac led to the hydrochloride salt 2Ab. A novel synthetic pathway to 6,9‐dihydroxybenzo[g]‐phthalazine‐5,10‐dione (21a) was developed. Conversion of 21a to the ditosylate 21b was readily accomplished. Treatment of 21b with N,N‐dimethylethylenediamine or N‐(t‐butoxycarbonyl)ethylenediamine led to 2Ca and 2Cc, respectively. Removal of the BOC‐protecting group from 2Cc with trifluoroacetic acid followed by ion‐exchange led to the hydrochloride salt 2Cb. Treatment of ditosylate 21b with N‐(t‐butoxycar‐bonyl)ethylenediamine also led to the mono‐substituted analogue 25a along with a small amount of the O‐S cleavage product 25b. Treatment of 25a with N,N‐dimethylethylenediamine led to the unsymmetrically substituted derivative 25c which was converted into the trifluoroacetate salt 25d.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.