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A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of 50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs.

trans-Cyanocombretastatin A-4 (trans-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2H)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2H)-1,2,3-triazole CA-4 analogues (8a-i, 9 and 11a-e) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI50 values in the low nanomolar range. The most potent compound, 8a, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2H)-1,2,3-triazole ring system. Compound 8a exhibited GI50 values of

A series of novel diarylacrylonitrile and trans-stilbene analogues of resveratrol has been synthesized and evaluated for their anticancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogues 3b and 4a exhibited the most potent anticancer activity of all the analogues synthesized in this study, with GI50 values of < 10 nM against almost all the cell lines in the human cancer cell panel. Compounds 3b and 4a were also screened against the acute myeloid leukemia (AML) cell line, MV4-11, and were found to have potent cytotoxic properties that are likely mediated through inhibition of tubulin polymerization. Results from molecular docking studies indicate a common binding site for 4a and 3b on the 3,3-tubulin heterodimer, with a slightly more favorable binding for 3b compared to 4a; this is consistent with the results from the microtubule assays, which demonstrate that 4a is more potent than 3b in inhibiting tubulin polymerization in MV4-11 cells. Taken together, these data suggest that diarylacrylonitriles 3b and 4a may have potential as antitubulin therapeutics for treatment of both solid and hematological tumors.

In the crystal structure of (I), the mol­ecules are linked into chains by N—H⋯O hydrogen bonds with (5) ring motifs. After the N-methyl­ation of structure (I), no hydrogen-bonding inter­actions were observed for structure (II)., The title compound, C19H17N3O3S (I), was prepared by a [3 + 2]cyclo­addition azide condensation reaction using sodium azide and l-proline as a Lewis base catalyst. N-Methyl­ation of compound (I) using CH3I gave compound (II), C20H19N3O3S. The benzo­thio­phene ring systems in (I) and (II) are almost planar, with r.m.s deviations from the mean plane = 0.0205 (14) in (I) and 0.016 (2) Å in (II). In (I) and (II), the triazole rings make dihedral angles of 32.68 (5) and 10.43 (8)°, respectively, with the mean planes of the benzo­thio­phene ring systems. The trimeth­oxy phenyl rings make dihedral angles with the benzo­thio­phene rings of 38.48 (4) in (I) and 60.43 (5)° in (II). In the crystal of (I), the mol­ecules are linked into chains by N—H⋯O hydrogen bonds with R 2 1(5) ring motifs. After the N-methyl­ation of structure (I), no hydrogen-bonding inter­actions were observed for structure (II). The crystal structure of (II) has a minor component of disorder that corresponds to a 180° flip of the benzo­thio­phene ring system [occupancy ratio 0.9363 (14):0.0637 (14)].

Use of a novel reagent has been established for the synthesis of a series of 4,5-diaryl-2H-1,2,3-triazoles (6a-i and 9a-e) from cyanostilbene analogs of benzo[b]thiophene, benzo[b]furan and indole, catalyzed by L-proline via Lewis base-catalyzed one-step [3+2]cycloaddition of azide. This method provides an efficient, simple and environmentally benign procedure that affords good yields and relatively short reaction times.

2H-1,2,3-Triazoles (2) were synthesized by [3+2] cycloaddition of (Z)-2,3-diaryl substituted acrylonitriles (1) with sodium azide and ammonium chloride in DMF/water. This method represents a facile and efficient reaction procedure for the synthesis of 4,5-diaryl-2H-1,2,3-triazoles in modest to good yields.

Trans-Resveratrol (tRes) has been shown to have powerful antioxidant, anti-inflammatory, anticarcinogenic, and antiaging properties; however, its use as a therapeutic agent is limited by its rapid metabolism into its conjugated forms by UDP-glucuronosyltransferases (UGTs). The aim of the current study was to test the hypothesis that the limited bioavailability of tRes can be improved by modifying its structure to create analogs which would be glucuronidated at a lower rate than tRes itself. In this work, three synthetic stilbenoids, (E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid (NI-12a), (E)-2,4-dimethoxy-6-(4-methoxystyryl)benzaldehyde oxime (NI-ST-05), and (E)-4-(3,5-dimethoxystyryl)-2,6-dinitrophenol (DNR-1), have been designed based on the structure of tRes and synthesized in our laboratory. UGTs recognize and glucuronidate tRes at each of the 3 hydroxyl groups attached to its aromatic rings. Therefore, each of the above compounds was designed with the majority of the hydroxyl groups blocked by methylation and the addition of other novel functional groups as part of a drug optimization program. The activities of recombinant human UGTs from the 1A and 2B families were examined for their capacity to metabolize these compounds. Glucuronide formation was identified using HPLC and verified by β-glucuronidase hydrolysis and LC-MS/MS analysis. NI-12a was glucuronidated at both the -COOH and -OH functions, NI-ST-05 formed a novel N-O-glucuronide, and no product was observed for DNR-1. NI-12a is primarily metabolized by the hepatic and renal enzyme UGT1A9, whereas NI-ST-05 is primarily metabolized by an extrahepatic enzyme, UGT1A10, with apparent Km values of 240 and 6.2 μM, respectively. The involvement of hepatic and intestinal UGTs in the metabolism of both compounds was further confirmed using a panel of human liver and intestinal microsomes, and high individual variation in activity was demonstrated between donors. In summary, these studies clearly establish that modified, tRes-based stilbenoids may be preferable alternatives to tRes itself due to increased bioavailability via altered conjugation.

Background: Naphthalene is a good structural replacement for the isovanillin moiety (i.e. the 3- hydroxy-4-methoxyphenyl unit) in the combretastatin A-4 molecule, a natural product structurally related to resveratrol, which consistently led to the generation of highly cytotoxic naphthalene analogues when combined with a 3,4,5-trimethoxyphenyl or related aromatic system. Also, the naphthalene ring system is present in many current drug molecules that are utilized for anti-tumor, anti-arrhythmia and antioxidant therapy. Objective: In our continuing quest to improve the potencies of naturally occurring anti-cancer molecules through chemical modification, we have now synthesized a small library of 2-naphthaleno trans- stilbenes and cyanostilbenes that are structurally related to both resveratrol and DMU-212, and have evaluated these novel analogs against a panel of 54 human tumor cell lines. Method: A series of 2-naphthaleno-containing trans-stilbenes 3a-3h (Scheme 1) were synthesized by Wittig reaction of a variety of aromatic substituted benzyl-triphenylphosphonium bromide reactants with 2- naphthaldehyde using n-BuLi as a base in THF. A second series of 2-naphthaleno trans-cyanostilbenes analogs 5a-5h was synthesized by reaction of 2-naphthaldehyde (2; 1 mmol) with an appropriately substituted 2- phenylacrylonitrile 4a-4h; 1 mmol) in 5% sodium methoxide/methanol. The reaction mixture was stirred at room temperature for 2-3 hours and the reaction allowed to go to completion (TLC monitoring), during which time the desired product precipitated out of the solution as a solid. The resulting precipitate was filtered off, washed with water and dried to yield the desired compound in yields ranging from 70-95% (Scheme 2). Results: The percentage growth inhibition of 54 human cancer cell lines in a primary NCI screen after exposure to compounds 3a, 3d, 5b and 5c was carried out. The results showed that only compounds 5b and 5c met the criteria for subsequent testing to determine growth inhibition values (GI50) in dose-response studies. At 10-5 M concentration, compounds 5b and 5c exhibited cytotoxic activity against leukemia cell lines HL-60(TB) and SR, lung cancer cell line NCI-H522, colon cancer cell lines COLO 205 and HCT-116, CNS-cancer cell line SF-539, melanoma cell line MDA-MB-435, and breast cancer cell line BT-549. The naphthalene trans-stilbene analogue 3a, exhibited significant growth inhibition against only one cell line, melanoma cell line MDA-MB-435 (96 % growth inhibition). Compound 3d was inactive in the 10-5 M single dose screen. Conclusion: We have synthesized a small set of novel 2-naphthaleno stilbenes and cyanostilbenes and evaluated several of these compounds for their anticancer properties against a panel of 54 human tumor cell lines. The most active analogs, 5b and 5c, showed significantly improved growth inhibition against the human cancer cells in the NCI panel when compared to DMU-212. Of these compounds, analog 5c was found to be the most potent anticancer agent and exhibited significant growth inhibitory effects against COLO 205, CNS SF 539 and melanoma SK-MEL 5 and MDA-MB-435 cell lines with GI50 values ≤ 25 nM. Analog 5b also exhibited GI50 values in the range 25-41 nM against CNS SF 295 and melanoma MDA-MB-435 and UACC-62 cell lines. Compounds 5b and 5c were also cytotoxic towards the MV4-11 leukemia cell line with LD50 value of 450 nM and 200 nM, respectively, and demonstrated >50% inhibition of tubulin polymerization at concentrations below their LD50 values in these cells. In silico docking studies suggest that compounds 5b and 5c bind favorably at the colchicine- binding pocket of the tubulin dimer, indicating that both 5b and 5c may inhibit tubulin polymerization through a mechanism similar to that exhibited by colchicine. Derivative 5c demonstrated more favorable binding based on the docking score and buried surface area, as compared to compound 5b, in agreement with the higher observed potency of 5c against a broader range of tumor cell lines. Based on these results, analog 5c is considered to be a lead compound for further optimization as a clinical candidate for treating a variety of cancers.

trans-Cyanocombretastatin A-4 (trans-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2H)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2H)-1,2,3-triazole CA-4 analogues (8a–i, 9 and 11a–e) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI50 values in the low nanomolar range. The most potent compound, 8a, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2H)-1,2,3-triazole ring system. Compound 8a exhibited GI50 values of

A small library of (Z)-2-(benzo[d][1,3]dioxol-5-yl) and (Z)-2,3-dihydrobenzo [b][1,4] dioxin-6-yl analogs of 2- and 3-phenylacetonitriles has been synthesized and evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The dihydrodioxin analog 3j and dioxol analogs 5e and 7e exhibited the most potent anti-cancer activity of all the analogs synthesized in this study, with GI50 values of

Cancer is the second most life threatening disease after cardiovascular disease, affecting more than six million people per year worldwide.1 Drastic changes in life style during the end of the 19th century has increased the risk of humans developing different types of cancers. Also, considerable effort has been put into identifying molecules with anti-cancer properties from both natural and synthetic sources. Indole and barbituric acids derivatives are known to have a wide range of beneficial biological activities such as anti-cancer,2 anti-inflammatory,3 anti-convulsant,4 anti-psychotic,5 anti-hypertensive,6 and anti-bacterial properties.7 Singh et al. have synthesized and evaluated some novel N-benzyl indole-barbituric acid hybrid molecules against a panel of 60 human tumor cell lines. They identified compound 1 (Fig. 1) as a promising lead compound with significant tumor growth inhibitory activity (GI50) against a variety of human cancer cell lines; the molecule also had good maximum tolerable dose (MTD) characteristics.8 Our laboratory has also reported on several novel indole barbiturates as anti-cancer and radio-sensitization agents9,10 (compound 2, Fig 1). Recently,11 we have reported that N-aroyl indole thiobarbituric acids (compound 3, Fig. 1) possess both anticancer and anti-inflammatory properties. Several of these analogs are also inhibitors of DNA repair and replication stress response polymerases.12 Figure 1 lead compounds from previous studies (1–3)8–10 In our continuing studies on improving the potencies of newly identified anti-cancer leads, we now report on the synthesis and antiproliferative properties of some aromatic substituted 5-(indolin-3-ylmethylene)-1,3-dimethylpyrimidine-2,4,6-triones as second generation indole barbituric acid hybrids. A series of N-benzylindole-3-carboxaldehydes (2a–i) were synthesized by reacting an appropriate indole carboxaldehyde (1a–c) with various aromatic substituted benzyl halides utilizing the phase transfer catalyst triethylbenzyl ammonium chloride (TEBAC) in a mixture of 50% w/v aq. NaOH solution and dichloromethane. The resulting N-benzyl products were obtained in 80–85% yield.5 The N-benzylindole-3-carboxaldehydes (2a–i) (1 mmol) were each then reacted with N,N-dimethylbarbituric acid (1.2 mmol) in methanol at room temperature to afford a series of 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethyl-pyrimidine-2,4,6-(1H,3H,5H)-trione analogs (3a–i) (Scheme 1) in 75–90% yield. The synthesized compounds were fully characterized by 1H NMR and 13C NMR spectrometric analysis.13 Scheme 1 Reagents and conditions: (a) appropriate benzyl halide, 50% NaOH, CH2Cl2, TEBAC, 2hrs; (b) dimethylbarbituric acid in methanol, room temp, 75–90% yield In vitro screening of the above compounds was carried out against a panel of 60 human tumor cell lines utilizing the procedure described by Rubinstein et al.14 Compounds 3a–i were initially screened at 10−5 M to determine growth inhibition and cytotoxicity properties. Compounds 3c, 3d, 3f and 3g showed more than 60% growth inhibition in at least eight cell lines from the panel of sixty cell lines, and were selected for a complete dose response study at five different concentrations, viz. 10−4 M, 10−5 M, 10−6 M, 10−7 M and 10−8 M. The growth inhibitory or cytotoxicity effect of the test compounds in the above cellular assay is measured by determining percentage cell growth (PG) inhibition. Optical density (OD) measurements of SRB-derived color just before exposing the cells to the test compound (ODtzero) and after 48hrs exposure to the test compound (ODtest) or the control vehicle (ODctrl) are recorded.15 Growth percentage is calculated utilizing one of the two formulas below. A negative growth percentage implies cytotoxicity. The four compounds selected for full dose response studies were effective against lung cancer cell line NCI-H226, renal cancer cell line A498 and breast cancer cell line MDA-MB-468 in the single dose screen (Table 2). Activities of all four compounds against tumor cell line A498 was good, with ~ −90 percentage growth at 10µM. Although compounds 3h and 3e were not selected for complete dose-response studies, compound 3h was effective against the A498 cell line (−95 percentage growth), while compound 3e was active against the MDA-MB-468 cell line (−71 percentage growth) (Table 2). Table 2 Percentage growth inhibition of five human cancer cell lines by compounds (3a– 3i)a at 10 µM Further evaluation of lead compounds 3c, 3d, 3f and 3g in the five dose screen showed that these compounds were very effective against five particular cancer cell lines: NCI-H460, OVCAR-5, A498, TK-10 and MDA-MB-468, with GI50 values in the nanomolar range. Breast cancer cell line MDA-MB-468 appeared to be the most sensitive to the growth inhibition effects of these compounds; 3c, 3d, 3f and 3g exhibited GI50 values of 30 nM, 40 nM, 60 nM, and 30 nM, respectively, with LC50 values of 620nM, 760nM, 700 nM, and 500 nM, respectively, against this cell type. Compounds 3c, 3d, 3f and 3g also exhibited good growth inhibition against renal cancer cell line A498, with GI50 values of 120nM, 60nM, 40nM, and 70 nM, respectively, and LC50 values of 690 nM, 527 nM, 640 nM, and 670 nM, respectively. All four compounds were active against renal cancer cell line TK-10 with GI50 values of 280 nM, 100 nM, 180 nM, and 590 nM, respectively, and also exhibited growth inhibitory effects against ovarian cancer cell line OVCAR-5 (GI50=70 nM, 20 nM, 160 nM, and 110 nM, respectively) and non-small cell lung cancer cell line NCI-H460 (GI50=910 nM, 810 nM, 400 nM, and 370 nM, respectively). Compound 3d also inhibited the growth of colon cancer cell line COLO 205 (GI50=630 nM) and melanoma cell line UACC-62 (GI50=900 nM). In conclusion, a series of novel aromatic substituted 5-((1-benzyl-1H-indol-3-yl)-methylene)-1,3-dimethylpyrimidine-2,4,6-(1H,3H,5H)-trione analogs have been synthesized and evaluated for growth inhibition properties against a panel of 60 human cancer cell lines, and their GI50 and LC50 values have been determined. Four lead compounds (3c, 3d, 3f and 3g) have been identified with GI50’s in the nanomolar range against 5 different cell lines. All four compounds exhibited GI50 values in the range 30–60 nM and 40–120 nM against breast cancer MDA-MB-468 and renal cancer A49 cell lines, respectively; compounds 3c and 3d afforded GI50 values of 70 nM and 20 nM, respectively, against the ovarian cancer cell line OVCAR-5. The above four compounds generally have superior GI50 values compared to the previous lead compound 1 against most of the cell lines in the 60 tumor cell line panel. The biggest difference was the GI50 value of compound 1 against renal cancer cell line A49 (GI50=300 nM) compared to GI50 values over the range 40–120 nM for compounds 3c, 3d, 3f, and 3g. These novel aromatic substituted 5-((1-benzyl-1H-indol-3-yl)-methyl-ene)-1,3-dimethylpyrimidine-2,4,6-(1H,3H,5H)-triones represent promising new analogs that may have clinical potential in treating a variety of solid tumors.

Use of a novel reagent has been established for the synthesis of a series of 4,5-diaryl-2H-1,2,3-triazoles (6a-i and 9a-e) from cyanostilbene analogs of benzo[b]thiophene, benzo[b]furan and indole, catalyzed by L-proline via Lewis base-catalyzed one-step [3+2]cycloaddition of azide. This method provides an efficient, simple and environmentally benign procedure that affords good yields and relatively short reaction times.

2H-1,2,3-Triazoles (2) were synthesized by [3+2] cycloaddition of (Z)-2,3-diaryl substituted acrylonitriles (1) with sodium azide and ammonium chloride in DMF/water. This method represents a facile and efficient reaction procedure for the synthesis of 4,5-diaryl-2H-1,2,3-triazoles in modest to good yields.

Use of a novel reagent has been established for the synthesis of a series of 4,5-diaryl-2H-1,2,3-triazoles (6a-i and 9a-e) from cyanostilbene analogs of benzo[b]thiophene, benzo[b]furan and indole, catalyzed by L-proline via Lewis base-catalyzed one-step [3+2]cycloaddition of azide. This method provides an efficient, simple and environmentally benign procedure that affords good yields and relatively short reaction times.

The title compound, C20H23N3O6·CH3OH, was synthesized by [3 + 2] cycloaddition of(Z)-2,3-bis(3,4,5-trimethoxyphenyl)acrylonitrile with sodium azide and ammonium chloride in DMF/water. The central nitrogen of the triazole ring is protonated. The dihedral angles between the triazole ring and the 3,4,5-trimethoxyphenyl ring planes are 34.31 (4) and 45.03 (5)°, while that between the 3,4,5-trimethoxyphenyl rings is 51.87 (5)°. In the crystal, the molecules, along with two methanol solvent molecules are linked into anR44(10) centrosymmetric dimer by N—H...O and O—H...N hydrogen bonds.

Melampomagnolide B (MMB) is a natural sesquiterpene structurally related to parthenolide (PTL). We have shown that MMB exhibits anti-leukemic properties similar to PTL. Unlike PTL, the presence of a primary hydroxyl group in the MMB molecule allows the opportunity for examining the biological activity of a variety of conjugated analogs of MMB. We have now synthesized a series of carbamate analogs of MMB and evaluated these derivatives for anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 6a and 6e exhibited promising anti-leukemic activity against human leukemia cell line CCRF-CEM with GI50 values of 680 and 620 nM, respectively. Analog 6a also showed GI50 values of 1.98 and 1.38 μM respectively, against RPMI-8226 and SR leukemia cell lines and GI50 values of 460 and 570 nM against MDA-MB-435 melanoma and MDA-MB-468 breast cancer cell lines, respectively. Analog 6e had GI50 values of 650 and 900 nM against HOP-92 non-small cell lung and RXF 393 renal cancer cell lines.

Our laboratory recently reported that a group of novel indole quinuclidine analogues bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analogue exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogues acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogues demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors.

A small library of N-benzyl indolequinuclidinone (IQD) analogs has been identified as a novel class of cannabinoid ligands. The affinity and selectivity of these IQDs for the two established cannabinoid receptor subtypes, CB1 and CB2, was evaluated. Compounds 8 (R=R(2)=H, R(1)=F) and 13 (R=COOCH3, R(1)=R(2)=H) exhibited high affinity for CB2 receptors with Ki values of 1.33 and 2.50 nM, respectively, and had lower affinities for the CB1 receptor (Ki values of 9.23 and 85.7 nM, respectively). Compound 13 had the highest selectivity of all the compounds examined, and represents a potent cannabinoid ligand with 34-times greater selectivity for CB2R over CB1R. These findings are significant for future drug development, given recent reports demonstrating beneficial use of cannabinoid ligands in a wide variety of human disease states including drug abuse, depression, schizophrenia, inflammation, chronic pain, obesity, osteoporosis and cancer.

Breast cancer is one of the most common non-cutaneous type of cancer in women in worldwide and a leading cause of cancer-related deaths, and is increasing year by year in almost every areas of the globe. Breast cancer is commonly classified into the following two major types: (1) non-invasive breast cancer (cancer cells are confined within the duct and lobules) and (2) invasive breast cancer (cancer cells invade through the walls of the duct or lobules and infiltrate the surrounding tissues). Various kinds of treatments are available for breast cancer, such as chemotherapy, radiotherapy and hormone therapy (Ragaz, 2009). Many indole derivatives are reported as potent breast cancer agents, such as aplysinopsin analogs and indole-3-carbinols. Aplysinopsins are indole-derived marine natural products. The parent aplysinopsin was isolated for the first time (Kazlauskas, et al, 1977) as the major metabolite of eight Indo-Pacific sponge species, which are representatives of the genus Thorecta. The N-1-unsubstituted aplysinopsins have generated considerable interest due to their potentially useful medicinal properties (Dobroslawa, et al, 2009). Aplysinopsin has been reported as a potent cytotoxic agent against the Kβ-cell line and methyl-aplysinopsins against L-1210 and Kβ-cell lines has been reported as potent cytotoxic agents (Hollenbeak & Schmitz, 1977), and the anticancer activities of aplysinopsin and methyl-aplysinopsins against both 1210and Kβ-cells has also been reported (Kondo et al. 1994). Indole-3-carbinol, a phytochemical derived from cruciferous vegetables such as broccoli and Brussel sprouts, exhibits potent antiproliferative effects against human breast cancer cells and has been shown to decrease metastatic spread of tumors in experimental animals (Brew, et al., 2010). From the above observations and as part of a program for the development of small molecules as potential anticancer treatments (Thirupathi Reddy, et al., 2010 and Narsimha Reddy et al., 2010), we initiated a drug discovery program to identify novel benzylaplysinopsin analogs as potent breast cancer agents. Combretastins are plant products from the South African tree Combretum caffrum. This compound was found to inhibit tubulin polymerization, and competitively inhibit the

Newly synthesized title compounds (III) are evaluated for in vitro cytotoxicity against a panel of 57 human tumor cell lines.