Rational design, synthesis, and in vivo evaluation of the antileukemic activity of six new alkylating steroidal esters

Steroidal esters of the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl)amino-phenyl]butanoic acid (2-PHE-BU)

“…As we have reported elsewhere, the modification of the B ring into a seven-membered lactam ring induces conformational changes in the steroidal part, which enhances the genotoxic and cytotoxic activity [36] as well as the invivo antileukemic potency [15] of the target steroidal esters. Especially, B,D-bilactam derivatives have shown diverse in-vivo toxicity and moderate to excellent antileukemic activity depending on the structural features of the conjugated nitrogen mustard [16,20,37].…”

“…In this direction, our group has published a series of studies related to steroidal esters of aromatic nitrogen mustards as antineoplastic, especially antileukemic, agents [15]. Our efforts have succeeded in the identification of potent and promising derivatives (Fig.…”

“…3b-Hydroxy-cholest-5-en-7-one [24], 3b-hydroxy-androst-5-en-7,17-dione [25], 3b-hydroxy-17b-acetamide-androst-5-en-7-one [15], 3b-hydroxy-17a-aza-D-homo-androst-5-en-7,17-dione [26], 3b-hydroxy-7a-aza-B-homo-cholest-5-en-7-one [27], 3b-hydroxy-7a-aza-B-homo-androst-5-en-7,17-dione [28], 3b-hydroxy-7a-aza-B-homo-17b-acetamide-androst-5-en-7-one [15], 3b-hydroxy-7a,17a-diaza-B,D-dihomoandrost-5-en-7,17-dione [28], 3b-hydroxy-17b-acetamide-androst-5-en [29], and 3b-hydroxy17a-aza-D-homo-androst-5-en-17-one [30] were prepared according to the procedures reported in the literature.…”

“…Our efforts have succeeded in the identification of potent and promising derivatives (Fig. 2) with enhanced activity and reduced toxicity compared with the corresponding nitrogen mustards against in-vitro and in-vivo experimental tumors [15,16]. Extensive structure-activity relationship (SAR) studies have shown unique structural features of both the steroidal part and the nitrogen mustard, which contribute positively to the bioactivity of the target steroidal esters [16][17][18][19][20].…”

Cytogenetic and Antineoplastic Effects of Modified Steroidal Alkylators

“…Nitrogen mustards are highly reactive compounds with an inherent chemical affinity toward the nucleophilic sites of several biomolecules such as plasma proteins; at the same time, they are rapidly hydrolyzed and in some cases are deactivated by cellular resistance mechanisms (Koutsourea et al, 2008a). These disadvantages result in a significant loss of the active drug before reaching the DNA target and at the same time increase their toxic effects.…”