A 3D QSAR Study of Betulinic Acid Derivatives as Anti-Tumor Agents Using Topomer CoMFA: Model Building Studies and Experimental Verification

Abstract

Betulinic acid (BA) is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis. Betulin (BE), the 28-hydroxyl analog of BA, is present in large amounts (up to 30% dry weight) in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as BA, yet exhibits no significant cytotoxicity. Topomer CoMFA studies were performed on 37 BA and BE derivatives and their in vitro anti-cancer activity results (reported as IC 50 values) against HT29 human colon cancer cells in the present study. All derivatives share a common pentacyclic triterpenoid core and the molecules were split into three pieces by cutting at the C-3 and C-28 sites with a consideration toward structural diversity. The analysis gave a leave-one-out cross-validation q 2 value of 0.722 and a non-cross-validation r 2 value of 0.974, which suggested that the model has good predictive ability (q 2 > 0.2). The contour maps illustrated that bulky and electron-donating groups would be favorable for activity at the C-28 site, and a moderately bulky and electronwithdrawing group near the C-3 site would improve this activity. BE derivatives were designed and synthesized according to the modeling result, whereby bulky electronegative groups (maleyl, phthalyl, and hexahydrophthalyl groups) were directly introduced at the OPEN ACCESSMolecules 2013, 18 10229 C-28 position of BE. The in vitro cytotoxicity values of the given analogs against HT29 cells were consistent with the predicted values, proving that the present topomer CoMFA model is successful and that it could potentially guide the synthesis of new betulinic acid derivatives with high anti-cancer activity. The IC 50 values of these three new compounds were also assayed in five other tumor cell lines. 28-O-hexahydrophthalyl BE exhibited the greatest anti-cancer activities and its IC 50 values were lower than those of BA in all cell lines, excluding DU145 cells.

Comparative Study of Green Sub- and Supercritical Processes to Obtain Carnosic Acid and Carnosol-Enriched Rosemary Extracts with in Vitro Anti-Proliferative Activity on Colon Cancer Cells

“…In another published work, Rzeski et al (2006) demonstrated that betulinic acid acts as an effective anticancer agent by inducing growth arrest and apoptosis in concentration-dependent manner, with HT-29 cells being particularly sensitive to this pentacyclic triterpenoid [60]. However, reported IC50 values for betulinic acid by different research groups for the same cell model (HT-29) are discordant (2.7 µM, [60]; 13.9 µM, [61]; and 32.7 µM, [62]). The extremely low aqueous solubility (<1 µM), high protein binding (>99%) and poor membrane permeability of this compound [63,64] could explain the lack of robustness in data obtained under slightly different culturing conditions.…”

Betulinic Acid and its Derivatives as Potential Antitumor Agents

“…In preliminary screening of antitumor activity of about 2500 plant extracts, BA attracted more attention because of its apparent activity against melanoma . Subsequent studies revealed that BA and its synthetic and naturally occurring derivatives were cytotoxic to an extensive variety of cancer cells including osteosarcoma, Ewing's sarcoma, fibrosarcoma, embryonal neuroblastoma, glioma, leukemia, as well as several carcinomas, such as lung, colon, breast, prostate, hepatocellular, bladder, head and neck, stomach, pancreatic, cerebroma, ovarian, and cervical carcinoma . The cytotoxicities of BA and BN toward cultured primary cancer cells from patient tumor tissues of ovarian carcinoma, cervical carcinoma, neuroblastoma, glioblastoma, and leukemia have also been reported …”

“…To the best of our knowledge, only one 3D‐QSAR analysis of the antitumor bioactivity of BA and its derivatives has been reported . Hence, we next focused on the 3D‐QSAR, aiming to reveal the essential structural features for increasing the antitumor bioactivities.…”

“…3D‐QSAR analysis, usually utilizing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), has been demonstrated to be a reliable tool for analysis of structure–cytotoxicity relationships . Only one previous report, however, using a Topomer CoMFA method, has developed a 3D‐QSAR analysis that provides a structure–cytotoxicity relationship study for 37 selected BA derivatives against human colon cancer HT29 cells . A 3D‐QSAR analysis of 62 selected BA derivatives against human ovarian A2780 cancer cell lines, utilizing both CoMFA and CoMSIA, was expected to be useful to explore the essential structural features associated with the antitumor bioactivities of BA derivatives and is presented in this paper.…”

Synthesis and Biological Evaluation of Oxygen‐containing Heterocyclic Ring‐fused 23‐Hydroxybetulinic Acid Derivatives as Antitumor Agents

“…The introduction of oxadiazole ring (21) caused slight decrease in the activity, and no major effect on activity was observed upon acetylation of C-23 hydroxyl group (20). Comparing the activity of C-17 ester or amide derivatives (22a-d, 24a-d) with that of compound 20, it could be found that all of the derivatives showed a better antiproliferative profile than 20.…”