Steroidal aromatase inhibitors type I inhibitors
Aromatase inhibitors are normally classified as steroidal (type I) or nonsteroidal (type II). Numerous steroidal agents have been developed that exhibit either competitive inhibition, irreversible inhibition, or mechanism-based inhibition of aromatase.24 Mechanism-based inhibitors are bound to the catalytic site of the enzyme, which transforms them into electrophilic intermediates that become irreversibly attached to the enzyme, blocking its activity, and they are known as ''aromatase inactivators.'' This type of inhibitors have distinct advantages in drug design, since they are highly enzyme specific, produce prolonged inhibition, and exhibit minimal toxicities, and for this reason the steroidal aromatase inhibitors in clinical use behave as mechanism-based irreversible inhibitors.25
Although the precise chemical details are sometimes not known, many types of compounds containing latent electrophilic groups intended to be activated by aromatase are known. The most relevant are summarized below.
4.2.1. C-19-modified substrate analogs
The first group steroidal aromatase inhibitors are C-19-modified substrate analogs. One example is the propargyl derivative plomestane, for which two main types of mechanisms have been proposed. The first one postulates its oxidation by aromatase to give the C-19 carbonyl derivative, leading to the Michael acceptor 3.22, a substrate for nucleophilic attack by nucleophiles at the enzyme active site. The second mechanism is based on the one proposed for the inactivation of cytochrome P450 enzymes by terminal acetylenic compounds and involves epox-idation of the acetylene chain by aromatase to give the unstable oxirene 3.24 that reacts with aromatase to give 3.27 following rearrangement to ketene 3.26 (Fig. 3.17). The development of plomestane as an antitumor drug was halted because of ''technical problems.'' 6
4.2.2. 4-Hydroxyandrostenedione derivatives
The main representative of this group is formestane. This compound was first described as a competitive inhibitor, but subsequent evidence proved that its binding to aromatase was irreversible. The presence of the C-19 methyl group is essential, since the 19-nor derivative is not an aromatase inactivator, and this suggests that the 19-oxygenated metabolites are the inactivating species. The 4-hydroxy group is also essential, and the ethers and esters of formestane at O-4 are inactive. One possible mechanism that is consistent with these
3.24
3.25
3.26
3.27
FIGURE 3.17 Aromatase inhibition by C-19-modified substrate analogues.
3.24
3.25
3.26
3.27
FIGURE 3.17 Aromatase inhibition by C-19-modified substrate analogues.
OH Formestane h3c o
Aromatase
OH Formestane
3.28
Aromatase
3.28
Cys i
Tautomerism
- NuH I
Cys i
Cys i
FIGURE 3.18 Aromatase inhibition by 4-hydroxyandrostenedione derivates.
observations is summarized in Fig. 3.18, although the low activity found for the formyl derivative 3.28 proposed as an intermediate would seem to cast doubt on this proposal.
Formestane is a second-generation steroidal aromatase inhibitor, and the first one to reach clinical use during the early 1990s.27 Its main drawback is that it must be administered intramuscularly in order to avoid its first-pass glucuroni-dation at the C-4 hydroxyl, a problem that renders it unsuitable for widespread clinical use.
4.2.3. Steroids with additional unsaturations at the A and B rings
The first member of this class of compounds to be recognized as an aromatase inhibitor was testolactone, and subsequently 1,4-androstadiene-3,17-dione. Among other more highly unsaturated compounds, the most relevant is the 6-methylene derivative, known as exemestane.28 The use of testolactone in the treatment of breast cancer started in 1960, although its ability to inhibit aromatase was not discovered until 1979. It is a weak inhibitor, with a moderate clinical response that has precluded its widespread use. Exemestane was approved more recently for clinical use in some countries and has the advantages over formestane of being more potent and, specially, of allowing oral administration.29
Testolactone 1,4-Androstadiene- CH2
3,17-dione Exemestane
Testolactone 1,4-Androstadiene- CH2
3,17-dione Exemestane
The presence of the double bond at C-1 is essential for activity, and it has been suggested that the mechanism of irreversible inactivation involves its oxidation to a cation radical that would then be intercepted by a nucleophilic group of the active site. The generation of this radical would be facilitated by stabilization of the unpaired electron by delocalization across the adjacent unsaturated carbonyl system (Fig. 3.19).
4.2.4. Structure-activity relationships in steroidal aromatase inhibitors
The spatial requirements for interaction of steroidal compounds with the active site of aromatase are very restrictive, allowing only small structural changes on the A ring and at C-19. Some exceptions to this rule are the incorporation of small polar substituents at the C-4 position, such as a hydroxyl group, or the addition of aryl functionalities at the 7-position of the steroid. Inhibitors with such modifications exhibit enhanced affinity for the enzyme.24 Several enzyme structure-function studies have revealed two regions that are important parts of the active site and contribute to the binding of the substrate and inhibitors: the I helix, that comprises the portion from Cys-299 to Ser-312, and a hydrophobic pocket that comprises the portion from Ile-474 to His-480. On the contrary, some 3D QSAR studies using steroidal aromatase inhibitors suggested that around the C-6 region of the steroids there are hydrophobic interactions involving the a-face and the p-face with highly hydrophobic aliphatic amino acids, namely Ile-305, Ala-306,
FIGURE 3.19 Inactivation of aromatase by exemestane.
FIGURE 3.19 Inactivation of aromatase by exemestane.
Thr-310, Val-369, and Leu-477. The aromatase selectivity can be attributed to the formation of a hydrogen bond between an acceptor group of the ligand and the hydroxyl group of Ser-478.30
Continue reading here: Anthracyclines And Their Analogs
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