An Efficient Synthetic Strategy for Obtaining 4-Methoxy Carbon Isotope Labeled Combretastatin A-4 Phosphate and Other Z-Combretastatins

Abstract

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]

Targeted Drug Delivery for Breast Cancer Treatment

“…For example, bevacizumab has severe side effects on patients, including hypertension, bleeding, and arterial and venous thromboembolism [60]. The use of Combretastatin and Vadimezan to disrupt tumorvasculature [66][67][68][69] has also failed due to their severe side effects [70]. Moreover, angiogenesis is involved in many important body processes, such as wound healing, heart and kidney function, fetal development, and reproduction.…”

A practical radiosynthesis of a tritium‐labelled fluorocombretastatin

“…The availability of a biologically active radiolabelled combretastatin would greatly enhance the understanding of the pharmacokinetics and pharmacodynamics of these types of molecules. Methods for the syntheses of radiolabelled analogues of CA4P and CA1P have been developed, and the synthesis of 14 C‐labelled combretastatin A‐1 (CA1) and CA1P has been accomplished …”