Daniel Morton

Novel aromatase inhibitors by structure-guided design.

Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.

Social Dominance in Female Monkeys: Dopamine Receptor Function and Cocaine Reinforcement

BACKGROUNDnBrain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement.nnnMETHODSnDA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001-.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered.nnnRESULTSnNeither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys.nnnCONCLUSIONSnThe relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males.

Convenient method for the functionalization of the 4- and 6-positions of the androgen skeleton

The preparation and reactivity of steroidal vinyldiazo compounds is reported, providing a convenient, substituent tolerant, chemo- and stereoselective entry into 4- and 6-substituted androgen analogues from a common precursor. Under dirhodium catalysis, O-H insertion occurs at the carbenoid site, leading to 4-substituted steroids, but under silver catalysis, O-H insertion occurs at the vinylogous position, leading to 6-substituted steroids.

Collective Approach to Advancing C–H Functionalization

C–H functionalization is a very active research field that has attracted the interest of scientists from many disciplines. This Outlook describes the collaborative efforts within the NSF CCI Center for Selective C–H Functionalization (CCHF) to develop catalyst-controlled selective methods to enhance the synthetic potential of C–H functionalization.

CH Functionalization: Collaborative Methods to Redefine Chemical Logic

In many fields of academic scientific research, collaborations come about quite naturally. One discipline, however, that has tended not to follow this pattern is organic synthesis. That is not to say that organic chemists don t collaborate, but synthetic organic chemistry is primarily considered an enabling science. Advances in synthesis empower research in many other fields, and synthetic organic chemists are often actively engaged in interdisciplinary collaboration. However, it is rare to find synthetic organic chemists collaborating with each other toward a goal within their own discipline. Many arguments could be put forth for this lack of cooperation, but perhaps the most convincing is that organic chemistry, compared to many other fields, when most effective, is readily accessible. It does not rely upon highly sophisticated instrumentation or facilities that are available only to a few. A fantastic new synthetic method would ideally be extremely easy to perform from readily available materials. So, what really distinguishes a research program in organic synthesis are the ideas behind the work. As a consequence, sharing one s most exciting research ideas and insights with other organic chemists is risky, because, in principle, it would not require too much effort for an organic chemist to take advantage of an open exchange of ideas with another. Hence, synthetic organic chemists need to establish a high level of trust before they can effectively collaborate within their own discipline.

Expanding the Carbene CH Insertion Toolbox

Transition-metal-stabilized carbenes, or carbenoids, have been the subject of significant interest in the synthetic community, being capable and effective intermediates in a multitude of transformations. Of particular note is their ability to perform C H insertion reactions in a highly stereoand enantioselective fashion. Two key techniques have emerged that influence the reactivity of these transient intermediates: 1) variation of the steric and electronic nature of the substituents that flank the carbene carbon and 2) the design of efficient catalysts that can stabilize and mediate the reactivity of the carbene. Early work in this area focused on the dirhodium-catalyzed reaction of acceptorand acceptor–acceptor-substituted carbenoids (Figure 1). These highly electrophilic carbenoids found