The present SAR study of combretastatin A-3 (3a) focused on replacement of the 3-hydroxyl group by a series of halogens. That approach with Z-stilbenes resulted in greatly enhanced (>10-100-fold) cancer cell growth inhibition against a panel of human cancer cell lines and the murine P388 lymphocytic leukemia cell line. Synthesis of the 3-fluoro-Z-stilbene designated fluorcombstatin (11a) and its potassium 3'-O-phosphate derivative (16c) by the route 7 --> 8a --> 11a --> 14 --> 16c illustrates the general synthetic pathway. The 3'-O-phosphoric acid ester (15) of 3-bromo-Z-stilbene 13a was also converted to representative cation salts to evaluate the potential for improved aqueous solubility, and the potassium salt (16 mg/mL in water) proved most useful. The fluoro (11a), chloro (12a), and bromo (13a) halocombstatins were nearly equivalent to combretastatin A-4 (1a) as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin. The tubulin binding in cell-free systems was also retained in human umbilical vein endothelial cells. All three halocombstatins retained the powerful human cancer cell line inhibitory activity of combretastatin A-4 (1a) and proved superior to combretastatin A-3 (3a). In addition, the halocombstatins targeted Gram-positive bacteria and Cryptococcus neoformans.

Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [ 11 C]-labeled derivative for position emission tomography (PET). In order to obtain a suitable precursor for addition of a [ 11 C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.In 1987, we reported 1 the isolation, structure, and synthesis of combretastatin A-1 (1c, CA1) from the subtropical tree Combretum caffrum (Eckl. and Zeyh.) Kuntze (Combretaceae)1b collected in southern Africa, and two years later combretastatin A-4 (1a, CA4) from the same source was isolated and synthesized. 2 Subsequently, both CA1 and CA4 were converted to phosphate prodrugs (1d, CA1P 3 and 1b, CA4P4) and developed5 to human cancer clinical trials.6 CA1P and CA4P are presently in Phase I/II and III cancer trials, respectively, and CA4P is also in Phase II human macular degeneration (leading cause of blindness)7 clinical trials. The potential of CA4P in treating other eye diseases such as diabetic retinopathy7d and retinoblastoma7b,e is also being developed. Presently, CA4P (a.k.a. Zybrestat) followed by CA1P is the lead among cancer vasculature disrupting drugs.8a-e A large number of other potentially important recent observations concerning medical applications of the leading combretastatins include evidence that CA4P is antiangiogenic,8f increases aberrant organization of metaphase chromosomes in non-small cell lung cancer cells,8g inhibits gastric cancer cell metastasis,8h and improves glucose tolerance in diabetic mice, which in turn suggests a possible new approach to treatment of type 2 diabetes. 8i The latter evidence provides another mechanistic parallel to resveratrol (2) 8j and suggests many other avenues for research from cancer prevention 8h to longevity. 8kBy 2000, positron emission tomography (PET) was already well established as a non-invasive technique for biomedical imaging, and its potential for necessary applications in preclinical and clinical research employing the lead combretastatins, particularly CA4P, was clearly evident. To follow is both a brief outline of the radiolabeling rationale and a practical synthetic route to employ as a model for later introduction of a [ 11 C]-isotope into CA4/CA4P. A [ 11 C]

Conditions to obtain two polymorphic forms by crystallization from solution were determined for the analgestic drug hydro­morphone. In both polymorphs, the hydro­morphone mol­ecules adopt very similar conformations with some small differences observed only in the N-methyl amine part of the mol­ecule. The crystal structures of both polymorphs feature chains of mol­ecules connected by hydrogen bonds

In the crystal structure of a semi-synthetic opioid drug buprenorphine, C29H41NO4 {systematic name: (2S)-2-[(5R,6R,7R,14S)-9α-cyclo­propyl­methyl-3-hy­droxy-6-meth­oxy-4,5-ep­oxy-6,14-ethano­morphinan-7-yl]-3,3-di­methyl­butan-2-ol}, the cyclo­propyl­methyl group is disordered over two sites with an occupancy factor of 0.611 (3) for the major component. One of the hy­droxy groups is involved in intra­molecular O—H⋯O hydrogen bond. The other hy­droxy group acts as a proton donor in an inter­molecular O—H⋯O inter­action that connects mol­ecules into a zigzag chain along the b axis.