DNA Phosphodiesterase 1. Tyrosyl DNA Phosphodiesterase 1 is a very im ADMET predicted profile-classification

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1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/ Al 10 November 2016 ( ) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/025 ( ) A61P 35/00 ( ) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/IB20 16/ KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 4 January 2016 ( ) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (72) Inventor; and kind of regional protection available): ARIPO (BW, GH, (71) Applicant : PEHL AN, Mustafa [CY/CY]; Bahadir GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, sok. no 10 k.kaymakli, Nicosia, MERSIN 10 TURKEY TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (CY). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (81) Designated States (unless otherwise indicated, for every LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, kind of national protection available): AE, AG, AL, AM, (54) Title: NANO FLORO TRICYCLOHEXANE [Continued on nextpage] (57) Abstract: This invention is about the discovery of a new drug molecule that will inhibit the enzyme Tyrosyl Results DNA Phosphodiesterase 1. Tyrosyl DNA Phosphodiesterase 1 is a very im ADMET predicted profile-classification portant enzyme in terms of metastatic Model Result Probability cancer treatment as it is involved in re pairing damaged DNA of cancer cells. When Cancer cells (tumors) are dam aged by Chemotherapeutic anti cancer drugs, tyrosyl DNA Phosphodiesterase 1 is activated and repairs damaged can cer cells. As a result, cancer continues spreading within the body. If Tyrosyl DNA Phosphodiesterase 1 could be stopped doing that, cancer would stop spreading and therefore the cancer Chemotherapy drugs will provide much better therapeutic effects that will lead to stopping cancer. For this reason, tar geting Tyrosyl DNA Phosphodiesterase 1 has always been a target for Scientists who work on the discovery of new [Continued on nextpage] 0 0 o

2 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). ~ th amended clarms (Art. 19(1)) upon request of the applicant, before the expiration of the Published: time j imit e f erre t0 i n Article 21(2)(a) with international search report (Art. 21(3)) drug molecules. The purpose of this study is to introduce such a new drug molecule with in silico computational results with the relevant data. The compound is l,8,8-trifluoro,l -trifluoromethyl,4a- (l,4,4-trifluorocyclohexyl)decalin.

3 NANO FLORO TRICYCLOHEXANE NEW DRUG DISCOVERY (NANO-FLORO-TRICYCLOHEXANE) BREAK THE RESISTANCE MECHANISM OF CANCER THAT WILL Inhibition of Tyrosyl DNA Phosphodiesterase 1 is involved in the repairement of cancer as it repairs irreversible top-1 DNA covalent complexes [ 1]. Tyrosyl DNA Phosphodiesterase 1 inhibition can also be beneficial for treating malignant glioma, as identified by Al-Keilani [2]. The aims of this study were to establish a way to computationally predict how this enzyme can be inhibited with a certain novel new drug molecule designed on computer to see what enzymatic activity it may have for specifically and inhibiting only Tyrosyl DNA Phosphodiesterase 1. The online software called "Swiss target predictor" [3] was then used to find such novel molecules, and in one of the trials, such a novel compound that has 95% inhibition efficacy against tyrosyl DNA Phosphodiesterase 1 has been discovered. The molecule was Nano Floro tricyclohexane and figure 1 shows the open formula fort his novel drug molecule along with its inhibition data. The open chemical formula (SMILES) of this molecule was then entered into the ADMET predictor software online to see what Pharmacokinetic effects it may have [4]. The result was that it was a partial inhibitor of glycoproteins which are responsible from clotting [5] No other potential side effects were shown. Figure 1 shows the organic structure of the new drug molecule (Nano-florotricyclohexane) and Figure 2 shows the enzymatic activity and inhibition efficacy of the new novel drug compound, whereas figure 3 provides ADME (Absorption, Distribution, Metabolism, Elimination) data of this compound. It is evidenced within this study that a novel effective new drug molecule has been discovered that would treat and cure cancer. In future, it is expected that this drug molecule could be synthesized and then enters clinical trials. It is also expected that this active drug, if successful by the end of clinical trials, should be given to patients suffering from cancer with moderate to high dose vitamin K to prevent inner bleeding as the molecule has potential of inhibiting glycoproteins that may result in thinning blood.

4 References: Thomas S. Dexheimer et al., Tyrosyl DNA Phosphodiesterase as an anticancer therapy, Anticancer Agents Med Chem May; 8(4): Role of Tyrosyl-DNA Phosphodiesterase I (TDP1 ) as a Prognostic and Predictiv Factor in Malignant Glioma, Al-Keilani (Iowa Research 201 3) Johan W.M. Heemskerk et al., Platelet Activation and Blood Coagulation, Thromb haemost 2002, 88;

5 Claims 1. This invention is a new drug molecule (Nano-floro-tricyclohexane) computationaly predicted to stop cancer from spreading. 2. The drug molecule is shown to highly and specifically inhibit the enzyme Tyrosyl DNA Phosphodiesterase 1, the enzyme that repairs damaged DNA of cancer cells, according to claim Two figures related to this new drug molecule (Nano-floro-tricyclohexane) have been provided, the former shows the efficacy and enzymatic inhibition levels of the new drug molecule, and the latter shows the Pharmacokinetic ADME (how the drug will be absorbed and work within the body) properties, based on claim This new drug molecule is the first in its own category as there are no other Tyrosyl DNA Phosphodiesterase 1 inhibitors in the market. 5. Once synthesized and clinically tried, this new drug, according to claim 1, will stop metastatis (spreading cancer) and in combination with other anti cancer (Chemotherapy) drug(s), it will provide rapid healing as the damaged DNA of cancer cells will not be repaired anymore, due to the inhibition of the enzyme human Tyrosyl DNA Phosphodiesterase 1. Therefore, synthesis and initiation of clinical trials in relation to this new drug molecule will be highly beneficial in terms of patients suffering from cancer.

6 AMENDED CLAIMS received by the International Bureau on 09 September ( ) This invention is a new drug molecule (1,8,8-trifluoro, 1 trifluoromethyl, 4a-(l,4,4-trifluorocyclohexyl) decalin) computationaly predicted to stop cancer from spreading. The drug molecule is shown to highly and specifically inhibit the enzyme Tyrosyl DNA Phosphodiesterase 1, the enzyme that repairs damaged DNA of cancer cells, according to claim 1. Two figures related to this new drug molecule (1,8,8-trifluoro, 1 trifluoromethyl, 4a-(l,4,4-trifluorocyclohexyl) decalin) have been provided, the former shows the efficacy and enzymatic inhibition levels of the new drug molecule, and the latter shows the Pharmacokinetic ADME (how the drug will be absorbed and work within the body) properties, based on claim 1. This new drug molecule is the first in its own category as there are no other Tyrosyl DNA Phosphodiesterase 1 inhibitors in the market. Once synthesized and clinically tried, this new drug, according to claim 1, will stop metastatis (spreading cancer) and in combination with other anti cancer (Chemotherapy) drug(s), it will provide rapid healing as the damaged DNA of cancer cells will not be repaired anymore, due to the inhibition of the enzyme human Tyrosyl DNA Phosphodiesterase 1. Therefore, synthesis and initiation of clinical trials in relation to this new drug molecule will be highly beneficial in terms of patients suffering from cancer. The synthesis steps for obtaining the molecule, (1,8,8-trifluoro, 1 trifluoromethyl, 4a-(l,4,4-trifluorocyclohexyl) decalin) will be provided here. However, it must be noted that, as the molecule (1,8,8-trifluoro, 1 trifluoromethyl, 4a-(l,4,4-trifluorocyclohexyl) decalin) is not similar to any other known molecule within the Chemical libraries, only gen eralised synthesis steps will be mentioned as a strategy for obtaining the molecule. These steps will require many transitional steps involving many reactions when the molecule is being synthesized in a Chemistry laboratory, and synthesizing this molecule may take very long time (from months to years). The exact Chemical amounts that should be added in each step and how exactly the molecule will be obtained in detail will need further strategies and discussions by qualified Scientists or Organic Chemists. Generalised Possible Synthesis steps as a strategy for obtaining the molecule is as follows: Obtain liquid Geosmin, a

7 herbal product, otherwise get any kind of sample molecule that has the basic structure of statins. Treat the sample of selection with Lithium Bromide (LiBr) or with Sodium Hydroxide (NaOH) for making a reduction reaction. (This will cause the molecule of selection to remain with a single Methyl group located as attached to certain Carbon atom of two cyclohexanes attached together). Flourounate the product by F 2 to get rid of that single methyl group. This will result in obtaining a molecule consisting of two cyclohexanes attached together, where CF 3 and F will be attached to a certain carbon atom in the first cyclohexane and where two Flourine (F) atoms will be attached to a certain Carbon atom of the second Cyclohexane. Upon completion of the previous step, add difluorinated Cyclohexane (Cyclohexane that has two Flourine atoms attached on the same Carbon atom) to the mixture. As a final step, fluorinate the resultant molecule as a whole with Flourination reaction, and the final product that will be obtained will be (1,8,8-trifluoro, 1 trifluoromethyl, 4a-(l,4,4-trifluorocyclohexyl) decalin).

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20 INTERNATIONAL SEARCH REPORT International application No PCT/IB2016/ A. CLASSIFICATION OF SUBJECT MATTER INV. A61K31/025 A61P35/00 ADD. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-Internal WPI Data, EMBASE, BIOSIS C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. WO 96/00568 Al (BELOV IGOR VYACHESLAVOVICH 1-5 [RU] ) 11 January 1996 ( ) the whole document J P H A (ASAHI GLASS CO LTD) February 1990 ( ) the whole document / XI Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents : "A" document defining the general state of the art which is not considered to be of particular relevance later document published after the international filing date or priority date and not in conflict with the application but cited to understand the principle or theory underlying the invention Έ " earlier application or patent but published o n or after the international document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" documentwhich may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is Ό " document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed document member of the same patent family ate of the actual completion of the international search Date of mailing of the international search report 25 August /09/2016 Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B Patentlaan 2 NL HV Rijswijk Tel. (+31-70) , Fax: (+31-70) Jakobs, Andreas

21 INTERNATIONAL SEARCH REPORT International application No PCT/IB2016/05Q016 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to olaim No. C. MARCHAND ET AL: " Identi f i cation of 1-5 phosphotyrosine mimeti c inhibi tors of human tyrosyl -DNA phosphodi esterase I by a novel AlphaScreen high-throughput assay", MOLECULAR CANCER THERAPEUTICS, vol. 8, no. 1, 1 January 2009 ( ), pages , XP , US ISSN: , D0I : / MCT the whole document EP Al ( ISC CHEMICALS LTD [GB] ) January 1988 ( ) the whole document

22 INTERNATIONAL SEARCH REPORT Information on patent family members International application No PCT/IB2016/ Patent document Publication Patent family Publication cited in search report date member(s) date WO Al U CI O Al P H A NONE EP Al CA C DE Dl EP Al GB A GR T P H B J P S A US A