Steroid and fatty acid contents from the leaves of Carica papaya.

AIM: To extract and identify the non-polar entities from the leaves of Carica papaya, a plant used for medicinal purpose as folk medicine. MATERIALS AND METHODS: Petroleum ether extract of the Carica papaya leaves was used for this study. Saponification process and methylation process was performed to separate fatty acids and unsaponifiable matters. Phytochemical constituents were separated using chemical process and separated fractions were analyzed by thin layer chromatography (TLC) and gas chromatography coupled with mass spectroscopy (GC-MS). RESULTS: The chemical composition of the steroids, triterpenoids and fatty acid methyl esters (FAMEs) in leaves of Carica papaya, which were analyzed by gas chromatography coupled with mass spectroscopy (GC-MS). A total of 15 fatty acid components were identified in saponifiable matter, from unsaponifiable portion 2 steroids (campesterol, ß- or γ-sitosterol), 1 triterpene (squalene), and 1 diterpene (phytol) were identified. CONCLUSIONS: The results indicate that the extract is rich in non-polar compounds. In this study, GC-MS method is at the central focus for identification of these phytoconstituents. The current method can be used for direct analysis of non-polar entities of plant material.

A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non-Small Cell Lung Cancer Cells.

The therapeutic effect in non-small cell lung cancer (NSCLC) patients is limited because of intrinsic and acquired resistance. Thus, an unmet need exists for the development of new drugs to improve the therapeutic efficacy in NSCLC patients. In this study, the novel small molecule indolizino[6,7-b]indole derivative BO-1978 was selected to evaluate its therapeutic effects on NSCLC and its preclinical toxicity in animal models. An in vitro cytotoxicity assay revealed that BO-1978 significantly suppressed the growth of various NSCLC cell lines with or without mutations in epidermal growth factor receptor (EGFR). Mechanistically, we demonstrated that BO-1978 exhibited multiple modes of action, including inhibition of topoisomerase I/II and induction of DNA cross-linking. Treatment of NSCLC cells with BO-1978 caused DNA damage, disturbed cell cycle progression, and triggered apoptotic cell death. Furthermore, BO-1978 significantly suppressed the growth of EGFR wild-type and mutant NSCLC tumors in xenograft tumor and orthotopic lung tumor models with negligible body weight loss. The combination of BO-1978 with gefitinib further suppressed EGFR mutant NSCLC cell growth in xenograft tumor and orthotopic lung tumor models. Preclinical toxicity studies showed that BO-1978 administration did not cause apparent toxicity in mice. Based on its significant therapeutic efficacy and low drug toxicity, BO-1978 is a potential therapeutic agent for treatment of NSCLC.

PI3K Inhibition Augments the Therapeutic Efficacy of a 3a-aza-Cyclopenta[α]indene Derivative in Lung Cancer Cells.

The synergistic targeting of DNA damage and DNA repair is a promising strategy for the development of new chemotherapeutic agents for human lung cancer. The DNA interstrand cross-linking agent BO-1509, a derivative of 3a-aza-cyclopenta[α]indene, was synthesized and combined with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 to treat human lung cancer cells. Our results showed that the BO-1509 and LY294002 combination synergistically killed lung cancer cells in culture and also suppressed the growth of lung cancer xenografts in mice, including those derived from gefitinib-resistant cells. We also found that LY294002 suppressed the induction of several DNA repair proteins by BO-1509 and inhibited the nuclear translocation of Rad51. On the basis of the results of the γH2AX foci formation assays, LY294002 apparently inhibited the repair of DNA damage that was induced by BO-1509. According to the complete blood profile, biochemical enzyme analysis, and histopathologic analysis of major organs, no apparent toxicity was observed in mice treated with BO-1509 alone or in combination with LY294002. Our results suggest that the combination of a DNA cross-linking agent with a PI3K inhibitor is a feasible strategy for the treatment of patients with lung cancer.

Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach.

A series of new, water-soluble phenyl N-mustard-benzenealkylamide conjugates containing hydrophilic ω-dialkylaminoalkylamide or ω-cyclic aminoalkylamide moieties were synthesized via a bioisostere approach. These compounds have a broad spectrum of antitumor activity against a panel of human tumor cell lines. Of these derivatives, compound 18b effectively suppressed the growth of colon cancer (HCT-116), prostate cancer (PC3), and lung cancer (H460) xenografts. The growth of HCT-116 xenografts was almost completely suppressed when co-treated with compound 18b and 5-fluorouracil. Furthermore, compound 18b can induce DNA cross-linking and cell-cycle arrest at the G2/M phase. Early preclinical studies, including pharmacokinetics in rats, inhibition of the hERG, and 14 days of acute intravenous injection toxicity, suggest that compound 18b is a promising candidate for further preclinical studies.

Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross-linking and topoisomerase I and II inhibition.

A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of ß-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT-29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT-29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase.

Synthesis and antitumor evaluation of novel benzo[d]pyrrolo[2,1-b]thiazole derivatives.

A series of novel 2,3-bis(hydroxymethyl)benzo[d]pyrrolo[2,1-b]thiazoles and their bis(alkylcarbamate) derivatives were synthesized starting from benzothiazole via reaction with dimethyl acetylenedicarboxylate (DMAD)/tetra-fluoro boric acid, catalytic hydrogenation, and alkylcarbamoylation. The anti-proliferative activity of these agents against human leukemia and various solid tumor cell growth in vitro was studied. The structure-activity relationship studies revealed that the bis(alkylcarbamates) derivatives are generally more cytotoxic than the corresponding bis(hydroxymethyl) congeners in inhibiting human lymphoblastic leukemia CCRF-CEM and various human solid tumor cell growth in culture. These agents have no cross-resistance to taxol or vinblastine. Studies on the therapeutic effect against human breast carcinoma MX-1 xenograft showed that complete tumor remission (CR) were achieved by treating with C1-4'-F- or C1-4'-Cl-Ph-bis(i-propylcarbamates) derivatives (19b and 19c, respectively) and more than 99% tumor suppression by the corresponding bis(ethylcarbamates) 18b and 18c at the maximal tolerated dose. Alkaline agarose gel shifting assay revealed that the newly synthesized compounds are able to induce DNA interstrand cross-linking. The present studies generated a series of new potent DNA interstrand cross-linking agents, which have potential for further antitumor drug development.