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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
  • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
  • C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
  • C07D311/48—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring with two such benzopyran radicals linked together by a carbon chain
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/56—Radicals substituted by sulfur atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

• the present invention relates to compounds for inhibition of uncontrolled cell proliferation, particularly cancer stem cells.
• the present invention also relates to the compounds for use in the treatment of cancer.
• Cancer is a condition in which abnormal cells proliferate and spread at any place in the body. In other words, cancer is an uncontrolled growth of abnormal cells. Cancer is a leading cause of death worldwide. It remains the second most dreadful disease in India, killing more than three million patients each year. It is of major concern in India and is reported to be one of the ten leading causes of deaths in India.
• CSCs and work either alone or in combination with the standard therapies to provide effective treatment option for the cancer patients.
• the present invention provides compounds for the treatment of cancer, particularly cancer stem cells that show preferential toxicity towards malignant cells, particularly in cancer cell lines such as breast cancer, and/or prostate cancer cell lines.
• E and Z is selected from C, O, N, S, salts of N such as N. HCl;
• Q is O, S, -CH 2 O-, -NY', wherein Y' is selected from -H, alkyl, SOOCH3;
• R 5 is -H, -CI, when E and/or Z is -C;
• R 6 and R 7 each independently is selected from -H, alkoxy, alkyl, substituted or unsubstituted aromatic group, -NF1 2 , -N0 2 , - NHCOCH 3 , -CN, -0-, halogen, -OCF 3 or R 6 and R 7 together form a heterocyclic ring;
• R 8 is -H, -CI, when E and/or Z is -C;
• R 9 is -CH2-0— CH2, -COOH, -X where can be F, CI, Br, alkyl such as -CH 3 , - OH, al
• X F, CI, Br, alkyl, acetyl, C 3 -C 8 acyl group;
• R 15 is selected from alkoxy, -OMe, -OH, -H, Br, NH 2 , X - F, CI, Br, alkyl, acetyl, C 3 -C 3 acyl group;
• R 16 is selected from -H, -CH 2 OH, -OH, alkyl, alkoxy;
• R 17 is selected from alkyl.
• R is selected from:
• R 11 and R 12 each independently is selected from -H, or R 11 and R 12 can be substituted or unsubstituted 5- or 6- membered ring such as lactone, -C(0)0-alkyl such as - C(0)OC 2 3 ⁇ 4;
• compound of Formula VII is providec
• compound of Formula Vlll is prov
• the present invention provides compounds V to XIV for use in treatment of cancer.
• compounds of Formula V to XIV for use in the treatment of cancer is provided.
• the cancer can be breast, oral, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, or stomach cancer.
• the compounds of Formula V or VI can be for use in the treatment of breast and/or prostate cancer.
• a pharmaceutical composition having a compound of Formula V to Formula XIV and pharmaceutically acceptable excipient including carrier, adjuvant, vehicle or mixtures thereof is provided.
• the composition of the present invention can be used in the treatment of cancer.
• the cancer includes breast, oral, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, or stomach cancer.
• the composition can be used for the treatment of breast and/or prostate cancer.
• a method of treating cancer by administering an effective amount of at least one of compounds of present invention is provided.
• a method of treating cancer including administering an effective amount of compound of formula V or VI is provided.
• the method of treatment including administering an effective amount of compound of formula V or VI can be for treating breast cancer and/ or a prostate cancer.
• Fig 1 Shows effect of compound of Formula V on cancer cell lines MDAMB231 and PC3 compared to standard chemo therapeutic drug Cisplatin in MTT assay.
• Fig 2. Shows effect of compound of Formula V on cancer cell lines MDAMB231 and PC3 compared to standard chemo therapeutic drug Cisplatin in soft Agar Assay.
• Fig 3 Shows the percentage viability of spheres of MDAMB231 in the presence of compound of Formula V compared to standard chemo therapeutic drug
• Fig 4 Shows that there is decrease in percentage viability of spheres of PC3 in presence of Formula V compared to standard chemotherapeutic drug Cisplatin.
• Fig 5 Shows the effect of compound of Formula VI on MDAMB231 and PC3 cancer cell lines compared to standard chemo therapeutic drug Cisplatin in MTT assay.
• Fig 6 Shows the effect of compound of Formula VI on MDAMB231 and PC3 cancer cell lines compared to standard chemo therapeutic drug Cisplatin in Soft Agar Assay.
• Fig 7 Shows that there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula VI compared to standard chemo therapeutic drug Cisplatin
• Fig 8 shows that there is decrease in percentage viability of spheres of PC3 in presence of compound of Formula VI compared to standard chemotherapeutic drug Cisplatin.
• Fig 9. Shows compound of Formula VII exhibits higher anticancer activity on MCF7, MDAMB231, PC3 and DU145 cell lines compared to standard chemo therapeutic drug Cisplatin in MTT assay.
• Fig 10. Shows that compound of Formula VII exhibits higher anticancer activity on MDAMB231, PC3 cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Fig.11 Shows there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula VII compared to standard chemo therapeutic drug Cisplatin.
• Fig 12 Shows that there is decrease in percentage viability of spheres of PC3 in presence of compound of Formula VII compared to standard chemotherapeutic drug Cisplatin.
• Fig 13 Shows that compound of Formula VIII exhibits higher anticancer activity on MCF7, MDAMB231, PC3 and DU145 cell lines compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Fig 14 Shows that compound of Formula VIII exhibits higher anticancer activity on MDAMB231, PC3 cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Figure 15 shows that there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula VIII compared to standard chemo therapeutic drug Cisplatin.
• Fig 16 shows that there is decrease in percentage viability of spheres of PC3 in presence of compound of Formula VIII compared to standard chemotherapeutic drug Cisplatin.
• Fig 17 Shows that compound of Formula ⁇ exhibits higher anticancer activity on MCF7, MDAMB231, PC3, DU145 cell lines compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Fig 18 Shows compound of Formula IX exhibits higher anticancer activity on MDAMB231, PC3 cell lines compared to standard therapeutic drug Cisplatin in Soft Agar Assay.
• Fig 19 Shows that there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula ⁇ compared to standard chemo therapeutic drug Cisplatin.
• Fig 20 indicates that there is decrease in percentage viability of spheres of PC3 in presence of compound of Formula IX compared to standard chemotherapeutic drug Cisplatin.
• Fig 21 Shows that compound of Formula X exhibits higher anticancer activity on MCF7, MDMB231, PC3, DU145 cell lines compared to standard chemo therapeutic drug Cisplatin in MTT assay.
• Fig 22 Shows that compound of Formula X exhibits higher anticancer activity on MDMB231, PC3 cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Fig 23 Shows that there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula X compared to standard chemo therapeutic drug Cisplatin.
• Fig 24 Shows that compound of Formula XI exhibits higher anticancer activity on MCF7, MDMB231, PC3, DU145 cell lines compared to standard chemo therapeutic drug Cisplatin in MTT Assay.
• Fig 25 Shows that compound of Formula XI exhibits higher anticancer activity MDMB231, PC3 cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Fig 26 Shows that compound of Formula XII exhibits higher anticancer activity on MCF7, MDMB231, PC3, DU145 cell lines compared to standard chemo therapeutic drug Cisplatin in MTT Assay
• Fig 27 Shows that compound of Formula XII exhibits higher anticancer activity on MDMB231, PC3 cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Fig 28 Shows that percentage viability of spheres of MDAMB231 in presence of compound of Formula XII is similar compared to standard chemo therapeutic drug Cisplatin.
• Fig 29 Shows that percentage viability of spheres of PC3 in presence compound of Formula XII is higher compared to standard chemotherapeutic drug Cisplatin.
• Fig 30 Shows that compound of Formula XIII exhibits higher anticancer activity on MDMB231, PC3, DU145 cell lines compared to standard chemo therapeutic drug Cisplatin in MTT assay
• Fig 31 Shows that compound of Formula XIII exhibits higher anticancer activity on MDMB231, PC3 cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Fig 32 Shows there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula XIII compared to standard chemo therapeutic drug Cisplatin.
• Fig 33 Shows that there is decrease in percentage viability of spheres of PC3 in presence of compound of Formula XIII compared to standard chemotherapeutic drug Cisplatin.
• Fig 34 Shows that compound of Formula XIV exhibits higher anticancer activity on MDMB231 cell line compared to standard chemo therapeutic drug Cisplatin in Soft Agar Assay.
• Fig.35 Shows that there is decrease in percentage viability of spheres of MDAMB231 in presence of compound of Formula XIV compared to standard chemotherapeutic drug Cisplatin.
• Fig.36 Shows that there is decrease in percentage viability of spheres of PC3 in presence of compound of Formula XIV compared to standard chemotherapeutic drug Cisplatin.
• the present invention relates to compounds for treating various conditions, particularly for inhibition of uncontrolled cell proliferation. Particularly the compounds are effective against cancer stem cells and treating cancer.
• the present invention relates to compound of Formula 1 :
• R 1 is selected from -H, -CH 2 OH
• R 2 is selected from— H, -OH, alkoxy, alkyl, acetyl, C 3 -Cs acyl group
• R is selected from alkoxy, alkyl, acetyl, C 3 -Cs acyl group
• R 4 is selected from -OH, F, -NH 2 , -NHCGCH 3 , alkyl, acetyl, C 3 -C 8 acyl group
• R 5 is H, CI
• R 6 and R 7 each independently is selected from H, alkyl, substituted or unsubstituted aromatic group, alkoxy, NH 2 , N0 2 , -NHCOCH 3 , -
• A is O, -NH, -N-alkyl;
• Q is O, S, -CH 2 0-;
• X is selected from CH 2 , O, N, S;
• E is selected from CH, O, N, S; and
• Z is selected from CH, O, N, S.
• the R 9 group is
• the present invention provides compounds of Formula III or salts thereof for treating various conditions, particularly for inhibition of uncontrolled cell proliferation.
• the compounds are effective against cancer stem cells.
• E and Z is selected from C, G, N, S, salts of N such as N. HCl; Q is O, S, -CH 2 O-, -NY', wherein Y' is selected from -H, alkvl; SOOCH3; R 5 is -H, -CI, when E and/or 7.
• R 6 and R each independently is selected from -H, alkoxy, alkyl, substituted or unsubstituted aromatic group, -NH 2 , -N0 2 , - NHCOCH 3 , -CN, -0-, halogen, -OCF 3 or R 6 and R 7 together form a heterocyclic ring;
• R 8 is -H, -CI, when E and/or Z is -C;
• R 9 is -CH2-0— CH2, -COOH, -X where X can be F, CI, Br, alkyl such as -CH 3 , -OH, alkoxy such as -OMe, NHCOCH 3 , H,
• NH 2 R 11 and R 12 each independently is selected from -FL R 11 and R can be substituted or unsubstituted 5- or 6- membered ring such as lactone, -C(0)0-alkyl such as -CtO)OC 2 H5 ;
• R is selected from:
• R 13 is selected from -OH, -NH 2 , -NHCOCH 3
• X F, CI, Br, alkyl, acetyl, C 3 -Cg acyl group
• R 14 is selected from alkoxy, -OMe, -OH, NH 2 - NHCOCH 3, X - F, CI, Br, alkyl, acetyl, C 3 -C 8 acyl group
• R 15 is selected from alkoxy, -OMe, -OH, -H, Br, NH 2 , X ⁇ F, CI, Br, alky
• R, R 6 , R', R 11 and R 12 have the meaning as assigned above.
• a compound of Formula V or salts thereof is provided to prevent cell proliferation:
• the compound of Formula V of the present invention are active on Breast and prostate cancer cell lines. Further, compound of Formula V is potent compared to standard chemotherapeutic drug Cisplatin. The compound of Formula V does not show activity on normal lymphocytes.
• a compound of Formula VI or salts thereof is provided to prevent cell proliferation:
• Compound of Formula VI shows activity in breast and prostate cancer cell lines. Further, compound of Formula VI is potent compared to standard chemotherapeutic drug Cisplatin. The compound of Formula VI does not show activity on normal lymphocytes.
• the present invention provides compounds that demonstrate anticancer and anti-cancer stem cell activity particularly in breast and prostate cancer cell lines.
• compound of formula VII is provided:
• Compound of Formula VII shows activity in breast and prostate cancer cell lines. The compound of Formula VII does not show activity on normal lymphocytes.
• the present invention provides compound of Formula VIII that prevents cell proliferation.
• Compound of Formula VIII shows activity in breast and prostate cancer cel l lines and does not show activity on normal lymphocytes.
• Compound IX of the present invention shows activity in breast and prostate cancer cell lines.
• compound of Formula X that prevents cell proliferation:
• Compound of formula X shows activity in breast and prostate cancer c lines and does not show activity in normal lymphocytes.
• the present invention provides compound Formula XI that prevents cell proliferation:
• Compound of formula XI shows acti vity in breast and prostate cancer cell lint
• the present invention provides compound Formula XII that prevents cell proliferation
• Compound of formula XII shows activity in breast and prostate cancer cell lines.
• the present invention provides compound of Formula XIII that prevents cell proliferation:
• Compound of formula XIII shows activity in breast and prostate cancer cell lines.
• Compound of formula XIV shows activity in breast cancer cell lines
• compounds of formula V to XIV of the present invention for use in the treatment of cancer is provided.
• the compound of Formula V and VI are provided for use in the treatment of cancer.
• the cancer can be the cancer is breast, oral, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, or stomach cancer.
• the compounds of Formula V and VI for use in the treatment of breast and/or prostate cancer is provided.
• compositions including the compounds of the present invention pharmaceutically acceptable excipient including carrier, adjuvant, vehicle or mixtures thereof are provided.
• pharmaceutical compositions including compounds of Formula V and VI pharmaceutically acceptable excipient including carrier, adjuvant, vehicle or mixtures thereof are provided.
• the pharmaceutical excipient can further include one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH- adjusting agents.
• the amount of compound in compositions may be such that it is effective to treat cancer in a subject in the need thereof.
• the composition may comprise between the biologically effective dose and the maximum tolerated dose of the compound of the invention or it's pharmaceutically acceptable salt, ester, or salt of an ester.
• compositions of this invention may be formulated for administration to a subject in the need thereof.
• the pharmaceutical compositions of the present invention may be formulated into a suitable dosage form to be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• Compositions of the present invention may be formulated into dosage forms including liquid, solid, and semisolid dosage forms.
• parenteral as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra- articular, intrasynovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the compositions are administered orally, intravenously or intraperitoneally.
• the present invention also includes the composition including the compounds of the present invention of Formula V to XIV, preferably compound of Formula V or VI for use in the treatment of cancer including cancer is breast, oral, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, or stomach cancer.
• the composition of the present invention is for the treatment of breast, and/or prostate cancer.
• a pharmaceutical composition comprises the aforesaid compounds with another active agent such as but are not limited to imatinib, nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A, retinoic acid, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate, tioguanine, vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, etoposide, teniposide, tafluposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, actinomycin, doxorubicin, da
• a method of treating cancer by administering an effective amount of compounds V to XIV of present invention is provided.
• a method of treating cancer comprising administering an effective amount of compound of formula V or VI is provided.
• the cancer can be breast, oral, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, or stomach cancer.
• the method of treatment of the present invention comprising administering an effective amount of compound of Formula V or VI can be for the treatment of breast and/ or prostate cancer.
• a method of inhibition of unregulated cell growth by administering effective amount of the compounds of the present invention is provided.
• the method of treating cancer by administering compounds of the present invention along with standard therapies or in combination with other drugs available for the treatment of cancer.
• Another embodiment of the invention provides for the use of the compounds in the treatment of unregulated cell growth, malaria, dengue.
• Step I Synthesis of 4-(benzo[d][l,3]dioxol-5-yl)naphthalen-l-ol
• Reagents and conditions a) NBS ' (N-BromosuccinimicSe), ACN (Acetonitrile, RT, 1,5 hr; b) PhCiTBr, K 2 CQ 3 , DMF (Dimethylfomianiide); c) Pd(PPh 3 )4- 3,4- (rnethylenedioxy). phenylboronie acid, jCOs, DME (Dimethoxyetharse); d) 10% Pd/e, EtOH:EtQAc (1 : 1) . , 60 °C, 60-80 psi.
• Reagents and conditions a) AC2O, pyridine; b) HBr*AcOH, DC (Dichioromet ane); c) 2,6-iutidine, Bu 4 NBr, EtGH, DCM; d) 1. MeONa, Me OH; 2. NaH, Mel, DMF (Dimethyiformamide); e) AeOH, Ac 2 0 ; Pyridine; ;f) HBfAcQH, DCM
• reaction mixture was diluted with dichloromethane (50 mL), washed with ice water (50 mL) followed b saturated NaHCOi solution (50 mL) and finally with brine solution (50 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give yellow colored liquid 12 as a product.
• Step III Synthesis of(3R r 41l,51l)-2 ⁇ (4 ⁇ henz0[dI L3 iUoxoi ⁇ 5
• Reagents and conditions a) BU 4 NB1-, 2M NaOH, DCM (Dichloromethane), RT; b) K 2 CO 3 MeOH, RT. b) K 2 C0 3 MeOH, RT.
• Reagents and conditions a) Br2, AcOH, 3 h; b) ethylene glycol, p-TSA (toluene sulfonic acid), toluene; c) n-BuLi, THF (tetrahydrofuran); d) piperinol, THF; e) diethyl acetylinedicarboxylate, AcOH, DCM; f) LiAlH 4 , THF.
• reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3 x 20 mL). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by titration with heptane and 18 is sufficiently pure to proceed to next step.
• Reagents and conditions a) a-phenylcyclopentaneacetic acid, DMAP (4- Dimethylaminopyridine), DCC ( ⁇ , ⁇ '-Dicyclohexylcarbodiimide), DCM (Dichloromethane), 0 °C overnight.
• Reagents and conditions a) l-methyl-2-pyrrolecarboxylic acid, DMAP, DCC, DCM, 0 °C overnight.
• Reagents and conditions a) Bu 4 NBr, 2M NaOH, DCM (Dichloromethane), RT; b) K 2 C0 3 MeOH, RT.
• Reagents and conditions a) NBS, DCM, 0°C, lhr; b) Tetrakis palladium (0), Na 2 C0 3 , H 2 0, DME (Dimethoxyethane), reflux, 12 hrs; c) furan-2-carbonyl chloride, Triethylamine, DCM, rt, 12 hrs
• Reagents and conditions a) K 2 C0 3 , DMF (Dimethylformamide), RT, 16 hrs; b) NBS, DCM, 0°C, lhr; c) Tetrakis palladium (0), Na 2 C0 3 , H 2 0, DME (Dimethoxyethane), reflux, 12 hrs; d) MeOH.HCl, RT, 2 hrs
• MTT assay is a simple and sensitive assay where, metabolic reducing activity of the cells is measured. The increase of this activity in time is taken as a parameter of cell growth. If treatment with a drug impairs this increase, the action may be a consequence of growth inhibition, cell killing or both.
• standard cytotoxic drug e.g. Cisplatin
• All cell lines were cultured in a 37°C incubator with a 5% C0 2 environment. Compounds were dissolved in DMSO with a concentration of 0.1M (stock solution). Cells were seeded into 96-well plates at suitable plating efficiency.
• the MTT procedure followed was as follows. Briefly, the cells were plated in 96 well plate as per predetermined plating efficiency(Tablel) The plates were then incubated for 24 hrs in 5% C0 2 atmosphere at 37°C. Appropriate concentrations of the drugs were then added to the plate and further incubation was carried out for 48 hrs (in 5% C0 2 atmosphere at 37 °C). The assay plate was then centrifuged twice at 3000 rpm for 3 mins and supernatant was then discarded.
• MTT solution 100 ul of MTT solution (0.5 mg/ml) was then added to each well of the plate and it was further incubated for 4hrs (in 5% C0 2 atmosphere at 37 °C.) Following 4 hr incubation, the plate was then centrifuged twice, and supernatant was aspirated off very carefully. 200 ul of DMSO was then added to each well to solublize. MTT crystals and mixed well by shaking the plate. XY graph of log Percent viability was then plotted against log drug concentration. IC50 (Drug concentration inhibiting the 50 % of cell population) was then calculated by regression analysis. Soft Agar Assay
• the Soft Agar Colony-formation Assay is an anchorage-independent growth assay in soft agar, which is one of the most stringent assays for detecting malignant transformation of cells.
• malignant cells are cultured with appropriate controls in soft agar medium for 1-2 weeks. Following this incubation period, formed colonies can either be analyzed morphologically using cell stain and quantifying the number of colonies formed.
• the results of the assay are comparable to those obtained after injecting tumorigenic cells into nude mice and is regarded as the "gold standard" for testing the tumorigenicity of cells in vitro (one of the important features of cancer stem cells, CSCs).
• Sphere assay measures the ability of Cancer Stem Cellss to form spheres in specially designed serum-free medium. We have used this assay to measure the killing efficiency of the test compounds as compared to the standard chemotherapeutic drug, Cisplatin.
• MEGM Limmosphere Media Preparation (For 100 mL): 1 g methyl cellulose autoclaved with magnetic stirrer Plain media (MEBM), 100 mL added and dissolved under magnetic stirring. After complete dissolution, add: FGF- 80 ⁇ , EGF- 40 ⁇ , Penstrep- 1 mL, Heparin- 400 ⁇ L.
• Prostosphere Media Preparation (For 100 mL): l g methyl cellulose autoclaved with magnetic stirrer, Plain media (Prostate Epithelial Basal Medium), 100 mL added and dissolved, under magnetic stirring. After complete dissolution, add: Insulin- 40 ⁇ , B27- 2 mL, EGF- 80 ⁇ ,, Penstrep- 1 ml. Procedure: -The cells were trypsinised and made into single-cell suspension by passing through cell strainers (100 ⁇ and 40 ⁇ , respectively), The cells were diluted at the concentration of 2000 cells/ 100 ⁇ . and suspended in either Mammosphere (for breast cell lines) or Prostosphere (for prostate cell lines).
• Human lymphocytes can be readily isolated from peripheral blood, centrifuged at low speeds for 3 Omins. Briefly, diluted defibrinated fresh blood was overlaid gradually on HiSeP LSM1077 and centrifuged at low speed for 30mins. The lymphocyte layer (the buffy coat) (Fig)was carefully removed in a new collection tube. The buffy coat was given another wash, by the diluent buffer, to reduce the platelet contamination. The supernatant was discarded, and the pellet was resuspended in diluent buffer. The viability was checked by Haemocytometer. Cells with Viability and Purity of 95% and more were considered for the assay.MTT assay was performed with these cells as described above with plating efficiency of 0.7million/ml.
• Table 3 indicates that activity of Formula V on breast cancer cell line is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 5 indicates the anticancer activity exhibited by Formula V is on breast cancer cell line MDAMB231 is higher than standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 6 indicates the anticancer activity of Formula V is higher on prostate cancer cell line in soft Agar Assay
• Table 7 indicates Formula V is effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisp latin.
• Table 8 indicates that Formula V is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin.
• Table 9 indicates that activity of Formula VI on breast cancer cell line is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 10 MTT Results of Formula VI for Prostate Cell lines IC50 in micromolar Table 10. indicates that activity of FORMULA VI on Prostrate cancer cell line is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• results of MTT assay indicates that compound of Formula VI exhibits higher anticancer activity on breast and prostate Cancer cell lines compared to standard chemo therapeutic drug Cisplatin.
• Table 11 indicates the anticancer activity of Formula VI is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 12 indicates the anticancer activity of Formula VI is higher on prostate cancer cell line PC3 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay The results Indicates that Formula VI exhibits higher anticancer activity on breast and prostate Cancer cell lines compared to standard chemotherapeutic drug Cisplatin in Soft Agar Assay.
• Table 13 indicates that Formula VI is more effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisplatin.
• Table 14 indicates that Formula VI is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin.
• Table 15 indicates that activity of Formula VII on breast cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 16 indicates that activity of Formula VII on prostate cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 17 inc icates the anticancer activity of FORMULA VI is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 19 indicates the that Formula VII is more effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisplatin.
• Table 21 indicates that activity of FORMULA VIII on breast cancer cell lines is higher compared to standard therapeutic drug Cisplatin in MTT assay.
• Table 22 indicates that activity of Formula VIII on prostate cancer cell lines is higher compared to standard therapeutic drug Cisplatin in MTT assay.
• Table 23 indicates the anticancer activity of Formula VIII is higher on breast cancer cell line MDAMB231 compared to standard therapeutic drug Cisplatin in soft Agar Assay.
• Table 24 indicates the anticancer activity of Formula VIII is higher on prostate cancer cell line PC3 compared to standard therapeutic drug Cisplatin in soft Agar Assay .
• Table 25 indicates the that Formula VIII is more effective on spheres of MDAMB231 compared to standard therapeutic drug Cisplatin
• Table 26 indicates that Formula VIII is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin
• Table 27 indicates that activity of FORMULA IX on breast cancer cell lines higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 28 indicates that activity of Formula IX on prostate cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 29 indicates the anticancer activity of Formula IX is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 30 Soft Agar Assay Results of Formula IX for Prostate Cell lines IC50 in micromolar Table 30 indicates the anticancer activity of Formula ⁇ is higher on prostate cancer cell line PC3 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 31 indicates that Formula IX is more effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisplatin.
• Table 32 indicates that Formula IX is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin.
• Table 33 indicates that activity of Formula X on breast cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 34 indicates that activity of Formula X on prostate cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 35 indicates the anticancer activity of Formula X is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 36 indicates the anticancer activity of Formula X is higher on prostate cancer cell line PC3 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 38 indicates that activity of ormula XI on breast cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT
• Table 39 indicates that activity of FORMULA XI on prostate cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 40 Soft Agar Assay Results of Formula XI for Breast Cell lines IC50 in micromolar Table 40 indicates the anticancer activity of Formula XI is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 41 indicates the anticancer activity of Formula XI is higher on prostate cancer cell line PC3 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 42 indicates that activity of Formula XII on breast cancer cell lines higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 43 MTT Results of Formula XII for Prostate Cell lines IC50 in micromolar
• Table 43 indicates that activity of Formula XII on prostate cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 44 Soft Agar Assay Results of Formula XII for Breast Cell lines IC50 in micromolar
• Table 44 indicates the anticancer activity of Formula XII is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 45 Soft Agar Assay Results of Formula XII for Prostate Cell lines IC50 in micromolar Table 45 indicates the anticancer activity of Formula XII is higher on prostate cancer cell line PC3 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 46 indicates that Formula XII is more effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisplatin.
• Table 47 indicates that Formula XII is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin.
• able 48 indicates that activity of Formula XIII on breast cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 49 indicates that activity of Formula XIII on prostate cancer cell lines is higher compared to standard chemotherapeutic drug Cisplatin in MTT assay.
• Table 50 indicates the anticancer activity of Formula XIII is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 51 Soft Agar Assay Results of Formula XIII for Prostate Cell lines IC50 in micromolar
• Table 51 indicates the anticancer activity of Formula XIII is higher on prostate cancer cell line PC3 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 52 indicates that Formula XIII is more effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisplatin.
• Table 53 indicates that Formula XIII is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin.
• Table 54 indicates the anticancer activity of Formula XIV is higher on breast cancer cell line MDAMB231 compared to standard chemotherapeutic drug Cisplatin in soft Agar Assay.
• Table 55 indicates that Formula XIV is more effective on spheres of MDAMB231 compared to standard chemotherapeutic drug Cisplatin.
• Table 56 indicates that Formula XIV is more effective on spheres of PC3 compared to standard chemotherapeutic drug Cisplatin.

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